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Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP

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Abstract

In recent years, there has been significant progress in the use of Cre-loxP technology for conditional gene expression in the inner ear. Here, we introduce the basic concepts of this powerful technology, emphasizing the differences between Cre and CreER. We describe the creation and Cre expression pattern of each Cre and CreER mouse line that has been reported to have expression in auditory and vestibular organs. We compare the Cre expression patterns between Atoh1-CreERTM and Atoh1-CreERT2 and report a new line, Fgfr3-iCreERT2, which displays inducible Cre activity in cochlear supporting cells. We also explain how results can vary when transgenic vs. knock-in Cre/CreER alleles are used to alter gene expression. We discuss practical issues that arise when using the Cre-loxP system, such as the use of proper controls, Cre efficiency, reporter expression efficiency, and Cre leakiness. Finally, we introduce other methods for conditional gene expression, including Flp recombinase and the tetracycline-inducible system, which can be combined with Cre-loxP mouse models to investigate conditional expression of more than one gene.

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Abbreviations

ABR:

Auditory brainstem response

BAC:

Bacterial artificial chromosome

βgal:

Beta-galactosidase

BMP:

Bone morphogenetic protein

BDNF:

Brain-derived neurotrophic factor

CFP:

Cyan fluorescent protein

Col1A1:

Alpha (1) collagen promoter

Col2A1:

Type II collagen promoter

DTA:

Diphtheria toxin fragment A

E:

Embryonic day

eGFP:

Enhanced green fluorescent protein

ES:

Embryonic stem cells

GER:

Greater epithelial ridge

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescent protein

GOI:

Gene of interest

Hsp90:

Heat shock protein 90

iCsp3:

Drug-inducible dimerizable caspase 3

IRES:

Internal ribosome entry site

KOMP:

NIH knockout mouse project

LER:

Lesser epithelial ridge

myo7a:

Myosin VIIa

NICD:

Notch intracellular domain

P:

Postnatal day

PAC:

Phage artificial chromosome

Pkd1:

Polycystic kidney disease 1

Rb:

Retinoblastoma protein

RFP:

Red fluorescent protein

rtTA:

Reverse tetracycline transactivator

SHH:

Sonic hedgehog

TRE:

Tetracycline responsive element

tTA:

Tetracycline transactivator

References

  • Editorial (2007) Toxic alert. Nature 449:378

  • Abraira VE, Satoh T, Fekete DM, Goodrich LV (2010) Vertebrate Lrig3–ErbB interactions occur in vitro but are unlikely to play a role in Lrig3-dependent inner ear morphogenesis. PLoS One 5:e8981

    Article  PubMed  CAS  Google Scholar 

  • Ahmed M, Wong EY, Sun J, Xu J, Wang F, Xu PX (2012) Eya1–Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Dev Cell 22:377–390

    Article  PubMed  CAS  Google Scholar 

  • Ahn S, Joyner AL (2004) Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell 118:505–516

    Article  PubMed  CAS  Google Scholar 

  • Ahn KJ, Passero F Jr, Crenshaw EB 3rd (2009) Otic mesenchyme expression of Cre recombinase directed by the inner ear enhancer of the Brn4/Pou3f4 gene. Genesis 47:137–141

    Article  PubMed  CAS  Google Scholar 

  • Akagi K, Sandig V, Vooijs M, Van der Valk M, Giovannini M, Strauss M, Berns A (1997) Cre-mediated somatic site-specific recombination in mice. Nucleic Acids Res 25:1766–1773

    Article  PubMed  CAS  Google Scholar 

  • Araki K, Imaizumi T, Okuyama K, Oike Y, Yamamura K (1997) Efficiency of recombination by Cre transient expression in embryonic stem cells: comparison of various promoters. J Biochem 122:977–982

    Article  PubMed  CAS  Google Scholar 

  • Arnold JS, Braunstein EM, Ohyama T, Groves AK, Adams JC, Brown MC, Morrow BE (2006) Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients. Hum Mol Genet 15:1629–1639

    Article  PubMed  CAS  Google Scholar 

  • Arnold K, Sarkar A, Yram MA, Polo JM, Bronson R, Sengupta S, Seandel M, Geijsen N, Hochedlinger K (2011) Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9:317–329

    Article  PubMed  CAS  Google Scholar 

  • Austin CP et al (2004) The Knockout Mouse Project. Nat Genet 36:921–924

    Article  PubMed  CAS  Google Scholar 

  • Auwerx J et al (2004) The European dimension for the mouse genome mutagenesis program. Nat Genet 36:925–927

    Article  PubMed  CAS  Google Scholar 

  • Badea TC, Wang Y, Nathans J (2003) A noninvasive genetic/pharmacologic strategy for visualizing cell morphology and clonal relationships in the mouse. J Neurosci 23:2314–2322

    PubMed  CAS  Google Scholar 

  • Bahloul A, Simmler MC, Michel V, Leibovici M, Perfettini I, Roux I, Weil D, Nouaille S, Zuo J, Zadro C, Licastro D, Gasparini P, Avan P, Hardelin JP, Petit C (2009) Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells. EMBO Mol Med 1:125–138

    Article  PubMed  CAS  Google Scholar 

  • Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007

    Article  PubMed  CAS  Google Scholar 

  • Barrionuevo F, Naumann A, Bagheri-Fam S, Speth V, Taketo MM, Scherer G, Neubuser A (2008) Sox9 is required for invagination of the otic placode in mice. Dev Biol 317:213–224

    Article  PubMed  CAS  Google Scholar 

  • Basch ML, Ohyama T, Segil N, Groves AK (2011) Canonical Notch signaling is not necessary for prosensory induction in the mouse cochlea: insights from a conditional mutant of RBPjkappa. J Neurosci 31:8046–8058

    Article  PubMed  CAS  Google Scholar 

  • Bouchard M, Souabni A, Mandler M, Neubuser A, Busslinger M (2002) Nephric lineage specification by Pax2 and Pax8. Genes Dev 16:2958–2970

    Article  PubMed  CAS  Google Scholar 

  • Bouchard M, Souabni A, Busslinger M (2004) Tissue-specific expression of Cre recombinase from the Pax8 locus. Genesis 38:105–109

    Article  PubMed  CAS  Google Scholar 

  • Brooker R, Hozumi K, Lewis J (2006) Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133:1277–1286

    Article  PubMed  CAS  Google Scholar 

  • Brown AS, Epstein DJ (2011) Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development. Development 138:3967–3976

    Article  PubMed  CAS  Google Scholar 

  • Buchholz F, Angrand PO, Stewart AF (1998) Improved properties of FLP recombinase evolved by cycling mutagenesis. Nat Biotechnol 16:657–662

    Article  PubMed  CAS  Google Scholar 

  • Burgess-Beusse B, Farrell C, Gaszner M, Litt M, Mutskov V, Recillas-Targa F, Simpson M, West A, Felsenfeld G (2002) The insulation of genes from external enhancers and silencing chromatin. Proc Natl Acad Sci U S A 99(Suppl 4):16433–16437

    Article  PubMed  CAS  Google Scholar 

  • Chen P, Johnson JE, Zoghbi HY, Segil N (2002) The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 129:2495–2505

    Article  PubMed  CAS  Google Scholar 

  • Chen CM, Krohn J, Bhattacharya S, Davies B (2011) A comparison of exogenous promoter activity at the ROSA26 locus using a PhiC31 integrase mediated cassette exchange approach in mouse ES cells. PLoS One 6:e23376

    Article  PubMed  CAS  Google Scholar 

  • Chow LM, Tian Y, Weber T, Corbett M, Zuo J, Baker SJ (2006) Inducible Cre recombinase activity in mouse cerebellar granule cell precursors and inner ear hair cells. Dev Dyn 235:2991–2998

    Article  PubMed  CAS  Google Scholar 

  • Coate TM, Raft S, Zhao X, Ryan AK, Crenshaw EB 3rd, Kelley MW (2012) Otic mesenchyme cells regulate spiral ganglion axon fasciculation through a Pou3f4/EphA4 signaling pathway. Neuron 73:49–63

    Article  PubMed  CAS  Google Scholar 

  • Cohen-Salmon M, Ott T, Michel V, Hardelin JP, Perfettini I, Eybalin M, Wu T, Marcus DC, Wangemann P, Willecke K, Petit C (2002) Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol 12:1106–1111

    Article  PubMed  CAS  Google Scholar 

  • Cox BC, Lenoir A, Zhang L, Steigelman KA, Zuo J (2010) Hair cell damage in the neonatal mouse cochlea using forced expression of diphtheria toxin. MidWinter Research Meeting of the Association for Research in Otolaryngology, Anaheim, CA

  • Danielian PS, Muccino D, Rowitch DH, Michael SK, McMahon AP (1998) Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol 8:1323–1326

    Article  PubMed  CAS  Google Scholar 

  • Dearman J, Zuo J (2010) Creating a hair cell specific Flp transgenic mouse. MidWinter Research Meeting of the Association for Research in Otolaryngology, Anaheim, CA

  • Deng M, Pan L, Xie X, Gan L (2010) Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear. Dev Biol 338:38–49

    Article  PubMed  CAS  Google Scholar 

  • Doerflinger NH, Macklin WB, Popko B (2003) Inducible site-specific recombination in myelinating cells. Genesis 35:63–72

    Article  PubMed  CAS  Google Scholar 

  • Doetzlhofer A, Basch ML, Ohyama T, Gessler M, Groves AK, Segil N (2009) Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev cell 16:58–69

    Article  PubMed  CAS  Google Scholar 

  • Dominguez-Frutos E, Lopez-Hernandez I, Vendrell V, Neves J, Gallozzi M, Gutsche K, Quintana L, Sharpe J, Knoepfler PS, Eisenman RN, Trumpp A, Giraldez F, Schimmang T (2011) N-myc controls proliferation, morphogenesis, and patterning of the inner ear. J Neurosci 31:7178–7189

    Article  PubMed  CAS  Google Scholar 

  • Dymecki SM (1996) Flp recombinase promotes site-specific DNA recombination in embryonic stem cells and transgenic mice. Proc Natl Acad Sci U S A 93:6191–6196

    Article  PubMed  CAS  Google Scholar 

  • Eagleson KL, Schlueter McFadyen-Ketchum LJ, Ahrens ET, Mills PH, Does MD, Nickols J, Levitt P (2007) Disruption of Foxg1 expression by knock-in of Cre recombinase: effects on the development of the mouse telencephalon. Neuroscience 148:385–399

    Article  PubMed  CAS  Google Scholar 

  • Engleka KA, Gitler AD, Zhang M, Zhou DD, High FA, Epstein JA (2005) Insertion of Cre into the Pax3 locus creates a new allele of Splotch and identifies unexpected Pax3 derivatives. Dev Biol 280:396–406

    Article  PubMed  CAS  Google Scholar 

  • Erway LC, Shiau YW, Davis RR, Krieg EF (1996) Genetics of age-related hearing loss in mice. III. Susceptibility of inbred and F1 hybrid strains to noise-induced hearing loss. Hear Res 93:181–187

    Article  PubMed  CAS  Google Scholar 

  • Fang J, Dearman J, Zuo J (2009) Characterization of the Brainbow transgenic labeling system in the mouse cochlea. Midwinter Research Meeting of the Association for Research in Otolaryngology, Baltimore, MD

  • Fang J, Zhang WC, Yamashita T, Gao J, Zhu MS, Zuo J (2012) Outer hair cell-specific prestin-CreER(T2) knockin mouse lines. Genesis 50:124–131

    Article  PubMed  CAS  Google Scholar 

  • Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V, Ottolenghi S, Taylor V, Nicolis SK (2009) Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci 12:1248–1256

    Article  PubMed  CAS  Google Scholar 

  • Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P (1996) Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci U S A 93:10887–10890

    Google Scholar 

  • Feil R, Wagner J, Metzger D, Chambon P (1997) Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun 237:752–757

    Article  PubMed  CAS  Google Scholar 

  • Feltri ML, D'Antonio M, Previtali S, Fasolini M, Messing A, Wrabetz L (1999) P0-Cre transgenic mice for inactivation of adhesion molecules in Schwann cells. Ann N Y Acad Sci 883:116–123

    Google Scholar 

  • Freyer L, Morrow BE (2010) Canonical Wnt signaling modulates Tbx1, Eya1, and Six1 expression, restricting neurogenesis in the otic vesicle. Dev Dyn 239:1708–1722

    Article  PubMed  CAS  Google Scholar 

  • Freyer L, Aggarwal V, Morrow BE (2011) Dual embryonic origin of the mammalian otic vesicle forming the inner ear. Development 138:5403–5414

    Article  PubMed  CAS  Google Scholar 

  • Friedman LM, Dror AA, Mor E, Tenne T, Toren G, Satoh T, Biesemeier DJ, Shomron N, Fekete DM, Hornstein E, Avraham KB (2009) MicroRNAs are essential for development and function of inner ear hair cells in vertebrates. Proc Natl Acad Sci U S A 106:7915–7920

    Article  PubMed  CAS  Google Scholar 

  • Fritzsch B, Dillard M, Lavado A, Harvey NL, Jahan I (2010) Canal cristae growth and fiber extension to the outer hair cells of the mouse ear require Prox1 activity. PLoS One 5:e9377

    Article  PubMed  CAS  Google Scholar 

  • Fujioka M, Tokano H, Fujioka KS, Okano H, Edge AS (2011) Generating mouse models of degenerative diseases using Cre/lox-mediated in vivo mosaic cell ablation. J Clin Invest 121:2462–2469

    Article  PubMed  CAS  Google Scholar 

  • Furr BJ, Jordan VC (1984) The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127–205

    Article  PubMed  CAS  Google Scholar 

  • Gao J, Wu X, Zuo J (2004) Targeting hearing genes in mice. Brain Res Mol Brain Res 132:192–207

    Article  PubMed  CAS  Google Scholar 

  • Giel-Moloney M, Krause DS, Chen G, Van Etten RA, Leiter AB (2007) Ubiquitous and uniform in vivo fluorescence in ROSA26-EGFP BAC transgenic mice. Genesis 45:83–89

    Article  PubMed  CAS  Google Scholar 

  • Gill-Sharma MK, Balasinor N, Parte P (2001) Effect of intermittent treatment with tamoxifen on reproduction in male rats. Asian J Androl 3:115–119

    PubMed  CAS  Google Scholar 

  • Gomez-Casati ME, Murtie J, Taylor B, Corfas G (2010) Cell-specific inducible gene recombination in postnatal inner ear supporting cells and glia. J Assoc Res Otolaryngol 11:19–26

    Article  PubMed  Google Scholar 

  • Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A 89:5547–5551

    Article  PubMed  CAS  Google Scholar 

  • Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769

    Article  PubMed  CAS  Google Scholar 

  • Grimsley-Myers CM, Sipe CW, Geleoc GS, Lu X (2009) The small GTPase Rac1 regulates auditory hair cell morphogenesis. J Neurosci 29:15859–15869

    Article  PubMed  CAS  Google Scholar 

  • Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ (2004) Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118:517–528

    Article  PubMed  CAS  Google Scholar 

  • Hartman BH, Reh TA, Bermingham-McDonogh O (2010) Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear. Proc Natl Acad Sci U S A 107:15792–15797

    Article  PubMed  CAS  Google Scholar 

  • Hatch EP, Urness LD, Mansour SL (2009) Fgf16(IRESCre) mice: a tool to inactivate genes expressed in inner ear cristae and spiral prominence epithelium. Dev Dyn 238:358–366

    Article  PubMed  CAS  Google Scholar 

  • Haugas M, Lillevali K, Hakanen J, Salminen M (2010) Gata2 is required for the development of inner ear semicircular ducts and the surrounding perilymphatic space. Dev Dyn 239:2452–2469

    Article  PubMed  CAS  Google Scholar 

  • Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244:305–318

    Article  PubMed  CAS  Google Scholar 

  • Hayashi S, Lewis P, Pevny L, McMahon AP (2002) Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain. Mech Dev 119(Suppl 1):S97–S101

    Article  PubMed  Google Scholar 

  • Hebert JM, McConnell SK (2000) Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev Biol 222:296–306

    Article  PubMed  CAS  Google Scholar 

  • Hurd EA, Poucher HK, Cheng K, Raphael Y, Martin DM (2010) The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear. Development 137:3139–3150

    Article  PubMed  CAS  Google Scholar 

  • Hwang CH, Guo D, Harris MA, Howard O, Mishina Y, Gan L, Harris SE, Wu DK (2010) Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice. Dev Dyn 239:505–513

    Article  PubMed  CAS  Google Scholar 

  • Indra AK, Warot X, Brocard J, Bornert JM, Xiao JH, Chambon P, Metzger D (1999) Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res 27:4324–4327

    Article  PubMed  CAS  Google Scholar 

  • Jacques BE, Montcouquiol ME, Layman EM, Lewandoski M, Kelley MW (2007) Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea. Development 134:3021–3029

    Article  PubMed  CAS  Google Scholar 

  • Jahan I, Kersigo J, Pan N, Fritzsch B (2010a) Neurod1 regulates survival and formation of connections in mouse ear and brain. Cell Tissue Res 341:95–110

    Article  PubMed  CAS  Google Scholar 

  • Jahan I, Pan N, Kersigo J, Fritzsch B (2010b) Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea. PLoS One 5:e11661

    Article  PubMed  CAS  Google Scholar 

  • Jayasena CS, Ohyama T, Segil N, Groves AK (2008) Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development 135:2251–2261

    Article  PubMed  CAS  Google Scholar 

  • Johnson KR, Zheng QY (2002) Ahl2, a second locus affecting age-related hearing loss in mice. Genomics 80:461–464

    Article  PubMed  CAS  Google Scholar 

  • Johnson KR, Zheng QY, Erway LC (2000) A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice. Genomics 70:171–180

    Article  PubMed  CAS  Google Scholar 

  • Jones C, Roper VC, Foucher I, Qian D, Banizs B, Petit C, Yoder BK, Chen P (2008) Ciliary proteins link basal body polarization to planar cell polarity regulation. Nat Genet 40:69–77

    Article  PubMed  CAS  Google Scholar 

  • Kawamoto S, Niwa H, Tashiro F, Sano S, Kondoh G, Takeda J, Tabayashi K, Miyazaki J (2000) A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre-mediated recombination. FEBS Lett 470:263–268

    Article  PubMed  CAS  Google Scholar 

  • Kazadi K, Loeuillet C, Deutsch S, Ciuffi A, Munoz M, Beckmann JS, Moradpour D, Antonarakis SE, Telenti A (2008) Genomic determinants of the efficiency of internal ribosomal entry sites of viral and cellular origin. Nucleic Acids Res 36:6918–6925

    Article  PubMed  CAS  Google Scholar 

  • Kiernan AE, Cordes R, Kopan R, Gossler A, Gridley T (2005) The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 132:4353–4362

    Article  PubMed  CAS  Google Scholar 

  • Kellendonk C, Tronche F, Casanova E, Anlag K, Opherk C, Schutz G (1999) Inducible site-specific recombination in the brain. J Molec Biol 285:175–182

    Google Scholar 

  • Kiernan AE, Xu J, Gridley T (2006) The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2:e4

    Article  PubMed  CAS  Google Scholar 

  • Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H, Bujard H (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A 93:10933–10938

    Article  PubMed  CAS  Google Scholar 

  • Kopecky B, Santi P, Johnson S, Schmitz H, Fritzsch B (2011) Conditional deletion of N-Myc disrupts neurosensory and non-sensory development of the ear. Dev Dyn 240:1373–1390

    Article  PubMed  CAS  Google Scholar 

  • Kopinke D, Brailsford M, Shea JE, Leavitt R, Scaife CL, Murtaugh LC (2011) Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas. Development 138:431–441

    Article  PubMed  CAS  Google Scholar 

  • Kopp JL, Dubois CL, Schaffer AE, Hao E, Shih HP, Seymour PA, Ma J, Sander M (2011) Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138:653–665

    Article  PubMed  CAS  Google Scholar 

  • Koundakjian EJ, Appler JL, Goodrich LV (2007) Auditory neurons make stereotyped wiring decisions before maturation of their targets. J Neurosci 27:14078–14088

    Article  PubMed  CAS  Google Scholar 

  • Kranz A, Fu J, Duerschke K, Weidlich S, Naumann R, Stewart AF, Anastassiadis K (2010) An improved Flp deleter mouse in C57Bl/6 based on Flpo recombinase. Genesis 48:512–520

    Article  PubMed  CAS  Google Scholar 

  • Kuhn R, Schwenk F, Aguet M, Rajewsky K (1995) Inducible gene targeting in mice. Science 269:1427–1429

    Google Scholar 

  • Kwan KM (2002) Conditional alleles in mice: practical considerations for tissue-specific knockouts. Genesis 32:49–62

    Article  PubMed  CAS  Google Scholar 

  • Langer SJ, Ghafoori AP, Byrd M, Leinwand L (2002) A genetic screen identifies novel non-compatible loxP sites. Nucleic Acids Res 30:3067–3077

    Article  PubMed  CAS  Google Scholar 

  • Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR (2005) Postnatal Isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653

    Article  PubMed  CAS  Google Scholar 

  • Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, Metzger D, Chambon P (2000) Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 407:633–636

    Article  PubMed  CAS  Google Scholar 

  • Li M, Tian Y, Fritzsch B, Gao J, Wu X, Zuo J (2004) Inner hair cell Cre-expressing transgenic mouse. Genesis 39:173–177

    Article  PubMed  CAS  Google Scholar 

  • Liu F, Woitge HW, Braut A, Kronenberg MS, Lichtler AC, Mina M, Kream BE (2004) Expression and activity of osteoblast-targeted Cre recombinase transgenes in murine skeletal tissues. Int J Dev Biol 48:645–653

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Owen T, Zhang L, Zuo J (2010) Dynamic expression pattern of Sonic hedgehog in developing cochlear spiral ganglion neurons. Dev Dyn 239:1674–1683

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Owen T, Fang J, Zuo J (2012a) Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner. PloS One 7:e34123

    Article  CAS  Google Scholar 

  • Liu Z, Owen T, Fang J, Srinivasan RS, Zuo J (2012b) In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation. Dev Dyn 241:684–696

    Article  PubMed  CAS  Google Scholar 

  • Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW (2007) Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450:56–62

    Article  PubMed  CAS  Google Scholar 

  • Lobe CG, Koop KE, Kreppner W, Lomeli H, Gertsenstein M, Nagy A (1999) Z/AP, a double reporter for Cre-mediated recombination. Dev Biol 208:281–292

    Article  PubMed  CAS  Google Scholar 

  • Lundell TG, Zhou Q, Doughty ML (2009) Neurogenin1 expression in cell lineages of the cerebellar cortex in embryonic and postnatal mice. Dev Dyn 238:3310–3325

    Article  PubMed  CAS  Google Scholar 

  • Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48:17–24

    Article  PubMed  CAS  Google Scholar 

  • Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR, Lein ES, Zeng H (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13:133–140

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Salas E (1999) Internal ribosome entry site biology and its use in expression vectors. Curr Opin Biotechnol 10:458–464

    Article  PubMed  CAS  Google Scholar 

  • Matei V, Pauley S, Kaing S, Rowitch D, Beisel KW, Morris K, Feng F, Jones K, Lee J, Fritzsch B (2005) Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Dev Dyn 234:633–650

    Article  PubMed  CAS  Google Scholar 

  • Mehasseb MK, Bell SC, Habiba MA (2009) The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse. Reproduction 138:341–350

    Article  PubMed  CAS  Google Scholar 

  • Mountford PS, Smith AG (1995) Internal ribosome entry sites and dicistronic RNAs in mammalian transgenesis. Trends Genet: TIG 11:179–184

    Article  PubMed  CAS  Google Scholar 

  • Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L (2007) A global double-fluorescent Cre reporter mouse. Genesis 45:593–605

    Article  PubMed  CAS  Google Scholar 

  • Nagy A (2000) Cre recombinase: the universal reagent for genome tailoring. Genesis 26:99–109

    Article  PubMed  CAS  Google Scholar 

  • Novak A, Guo C, Yang W, Nagy A, Lobe CG (2000) Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28:147–155

    Article  PubMed  CAS  Google Scholar 

  • Nyabi O, Naessens M, Haigh K, Gembarska A, Goossens S, Maetens M, De Clercq S, Drogat B, Haenebalcke L, Bartunkova S, De Vos I, De Craene B, Karimi M, Berx G, Nagy A, Hilson P, Marine JC, Haigh JJ (2009) Efficient mouse transgenesis using Gateway-compatible ROSA26 locus targeting vectors and F1 hybrid ES cells. Nucleic Acids Res 37:e55

    Article  PubMed  CAS  Google Scholar 

  • Oesterle EC, Chien WM, Campbell S, Nellimarla P, Fero ML (2011) p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary. Cell cycle 10:1237–1248

    Article  PubMed  CAS  Google Scholar 

  • Ohlemiller KK (2004) Age-related hearing loss: the status of Schuknecht's typology. Curr Opin Otolaryngol Head Neck Surg 12:439–443

    Article  PubMed  Google Scholar 

  • Ohyama T, Groves AK (2004) Generation of Pax2-Cre mice by modification of a Pax2 bacterial artificial chromosome. Genesis 38:195–199

    Article  PubMed  CAS  Google Scholar 

  • Ohyama T, Mohamed OA, Taketo MM, Dufort D, Groves AK (2006) Wnt signals mediate a fate decision between otic placode and epidermis. Development 133:865–875

    Article  PubMed  CAS  Google Scholar 

  • Ohyama T, Basch ML, Mishina Y, Lyons KM, Segil N, Groves AK (2010) BMP signaling is necessary for patterning the sensory and nonsensory regions of the developing mammalian cochlea. J Neurosci 30:15044–15051

    Article  PubMed  CAS  Google Scholar 

  • Ovchinnikov DA, Deng JM, Ogunrinu G, Behringer RR (2000) Col2a1-directed expression of Cre recombinase in differentiating chondrocytes in transgenic mice. Genesis 26:145–146

    Article  PubMed  CAS  Google Scholar 

  • Pan W, Jin Y, Stanger B, Kiernan AE (2010) Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear. Proc Natl Acad Sci U S A 107:15798–15803

    Article  PubMed  CAS  Google Scholar 

  • Pan N, Jahan I, Kersigo J, Kopecky B, Santi P, Johnson S, Schmitz H, Fritzsch B (2011) Conditional deletion of Atoh1 using Pax2-Cre results in viable mice without differentiated cochlear hair cells that have lost most of the organ of Corti. Hear Res 275:66–80

    Article  PubMed  CAS  Google Scholar 

  • Perrin BJ, Sonnemann KJ, Ervasti JM (2010) beta-actin and gamma-actin are each dispensable for auditory hair cell development but required for Stereocilia maintenance. PLoS Genet 6:e1001158

    Article  PubMed  CAS  Google Scholar 

  • Pirvola U, Ylikoski J, Trokovic R, Hebert JM, McConnell SK, Partanen J (2002) FGFR1 is required for the development of the auditory sensory epithelium. Neuron 35:671–680

    Article  PubMed  CAS  Google Scholar 

  • Raft S, Koundakjian EJ, Quinones H, Jayasena CS, Goodrich LV, Johnson JE, Segil N, Groves AK (2007) Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. Development 134:4405–4415

    Article  PubMed  CAS  Google Scholar 

  • Rawlins EL, Clark CP, Xue Y, Hogan BL (2009) The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136:3741–3745

    Article  CAS  PubMed  Google Scholar 

  • Raymond CS, Soriano P (2007) High-efficiency FLP and PhiC31 site-specific recombination in mammalian cells. PLoS One 2:e162

    Article  PubMed  CAS  Google Scholar 

  • Rickheit G, Maier H, Strenzke N, Andreescu CE, De Zeeuw CI, Muenscher A, Zdebik AA, Jentsch TJ (2008) Endocochlear potential depends on Cl− channels: mechanism underlying deafness in Bartter syndrome IV. EMBO J 27:2907–2917

    Article  PubMed  CAS  Google Scholar 

  • Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11:1392–1401

    Article  PubMed  CAS  Google Scholar 

  • Rocha-Sanchez SM, Morris KA, Kachar B, Nichols D, Fritzsch B, Beisel KW (2007) Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia. Brain Res 1139:117–125

    Article  PubMed  CAS  Google Scholar 

  • Rose MF, Ahmad KA, Thaller C, Zoghbi HY (2009) Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1. Proc Natl Acad Sci U S A 106:22462–22467

    Article  PubMed  CAS  Google Scholar 

  • Sage C, Huang M, Karimi K, Gutierrez G, Vollrath MA, Zhang DS, Garcia-Anoveros J, Hinds PW, Corwin JT, Corey DP, Chen ZY (2005) Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science 307:1114–1118

    Article  PubMed  CAS  Google Scholar 

  • Sage C, Huang M, Vollrath MA, Brown MC, Hinds PW, Corey DP, Vetter DE, Chen ZY (2006) Essential role of retinoblastoma protein in mammalian hair cell development and hearing. Proc Natl Acad Sci U S A 103:7345–7350

    Article  PubMed  CAS  Google Scholar 

  • Sakai K, Miyazaki J (1997) A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem Biophys Res Commun 237:318–324

    Article  CAS  PubMed  Google Scholar 

  • Sauer B, Henderson N (1989) Cre-stimulated recombination at loxP-containing DNA sequences placed into the mammalian genome. Nucleic Acids Res 17:147–161

    Google Scholar 

  • Schaft J, Ashery-Padan R, van der Hoeven F, Gruss P, Stewart AF (2001) Efficient FLP recombination in mouse ES cells and oocytes. Genesis 31:6–10

    Article  PubMed  CAS  Google Scholar 

  • Schultz JM et al (2009) Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet 85:25–39

    Article  PubMed  CAS  Google Scholar 

  • Shen L, Nam HS, Song P, Moore H, Anderson SA (2006) FoxG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits. Hippocampus 16:875–890

    Article  PubMed  CAS  Google Scholar 

  • Siegenthaler JA, Tremper-Wells BA, Miller MW (2008) Foxg1 haploinsufficiency reduces the population of cortical intermediate progenitor cells: effect of increased p21 expression. Cerebr Cortex 18:1865–1875

    Article  Google Scholar 

  • Sipe CW, Lu X (2011) Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms. Development 138:3441–3449

    Article  PubMed  CAS  Google Scholar 

  • Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143:134–144

    Article  PubMed  CAS  Google Scholar 

  • Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21:70–71

    Article  PubMed  CAS  Google Scholar 

  • Soukup GA, Fritzsch B, Pierce ML, Weston MD, Jahan I, McManus MT, Harfe BD (2009) Residual microRNA expression dictates the extent of inner ear development in conditional Dicer knockout mice. Dev Biol 328:328–341

    Article  PubMed  CAS  Google Scholar 

  • Sousa VH, Miyoshi G, Hjerling-Leffler J, Karayannis T, Fishell G (2009) Characterization of Nkx6-2-derived neocortical interneuron lineages. Cerebr Cortex 19(Suppl 1):i1–10

    Article  Google Scholar 

  • Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM, Costantini F (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM, Oliver G (2007) Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 21:2422–2432

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan RS, Geng X, Yang Y, Wang Y, Mukatira S, Studer M, Porto MP, Lagutin O, Oliver G (2010) The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev 24:696–707

    Article  PubMed  CAS  Google Scholar 

  • Steigelman KA, Lelli A, Wu X, Gao J, Lin S, Piontek K, Wodarczyk C, Boletta A, Kim H, Qian F, Germino G, Geleoc GS, Holt JR, Zuo J (2011) Polycystin-1 Is required for stereocilia structure but not for mechanotransduction in inner ear hair cells. J Neurosci 31:12241–12250

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Tang W, Chang Q, Wang Y, Kong W, Lin X (2009) Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea. J Comp Neurol 516:569–579

    Article  PubMed  CAS  Google Scholar 

  • Szeto IY, Leung KK, Sham MH, Cheah KS (2009) Utility of HoxB2 enhancer-mediated Cre activity for functional studies in the developing inner ear. Genesis 47:361–365

    Article  PubMed  CAS  Google Scholar 

  • Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsani D, Fu Y, Lu J, Lin Y, Miyoshi G, Shima Y, Fishell G, Nelson SB, Huang ZJ (2011) A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71:995–1013

    Article  PubMed  CAS  Google Scholar 

  • Tian Y, Li M, Fritzsch B, Zuo J (2004) Creation of a transgenic mouse for hair-cell gene targeting by using a modified bacterial artificial chromosome containing Prestin. Dev Dyn 231:199–203

    Article  PubMed  CAS  Google Scholar 

  • Tian Y, James S, Zuo J, Fritzsch B, Beisel KW (2006) Conditional and inducible gene recombineering in the mouse inner ear. Brain Res 1091:243–254

    Article  PubMed  CAS  Google Scholar 

  • Vooijs M, Jonkers J, Berns A (2001) A highly efficient ligand-regulated Cre recombinase mouse line shows that LoxP recombination is position dependent. EMBO Rep 2:292–297

    Article  PubMed  CAS  Google Scholar 

  • Vooijs M, Ong CT, Hadland B, Huppert S, Liu Z, Korving J, van den Born M, Stappenbeck T, Wu Y, Clevers H, Kopan R (2007) Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 134:535–544

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Chang Q, Tang W, Sun Y, Zhou B, Li H, Lin X (2009) Targeted connexin26 ablation arrests postnatal development of the organ of Corti. Biochem Biophys Res Commun 385:33–37

    Article  PubMed  CAS  Google Scholar 

  • Weber T, Corbett MK, Chow LM, Valentine MB, Baker SJ, Zuo J (2008) Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells. Proc Natl Acad Sci U S A 105:781–785

    Article  PubMed  CAS  Google Scholar 

  • Weston MD, Pierce ML, Jensen-Smith HC, Fritzsch B, Rocha-Sanchez S, Beisel KW, Soukup GA (2011) MicroRNA-183 family expression in hair cell development and requirement of microRNAs for hair cell maintenance and survival. Dev Dyn 240:808–819

    Article  PubMed  CAS  Google Scholar 

  • Willott JF, Tanner L, O'Steen J, Johnson KR, Bogue MA, Gagnon L (2003) Acoustic startle and prepulse inhibition in 40 inbred strains of mice. Behav Neurosci 117:716–727

    Article  PubMed  Google Scholar 

  • Winter H, Ruttiger L, Muller M, Kuhn S, Brandt N, Zimmermann U, Hirt B, Bress A, Sausbier M, Conscience A, Flamant F, Tian Y, Zuo J, Pfister M, Ruth P, Lowenheim H, Samarut J, Engel J, Knipper M (2009) Deafness in TRbeta mutants is caused by malformation of the tectorial membrane. J Neurosci 29:2581–2587

    Article  PubMed  CAS  Google Scholar 

  • Wunderlich FT, Wildner H, Rajewsky K, Edenhofer F (2001) New variants of inducible Cre recombinase: a novel mutant of Cre-PR fusion protein exhibits enhanced sensitivity and an expanded range of inducibility. Nucleic Acids Res 29:E47

    Article  PubMed  CAS  Google Scholar 

  • Xu H, Chen L, Baldini A (2007) In vivo genetic ablation of the periotic mesoderm affects cell proliferation survival and differentiation in the cochlea. Dev Biol 310:329–340

    Article  PubMed  CAS  Google Scholar 

  • Xuan S, Baptista CA, Balas G, Tao W, Soares VC, Lai E (1995) Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres. Neuron 14:1141–1152

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto N, Okano T, Ma X, Adelstein RS, Kelley MW (2009) Myosin II regulates extension, growth and patterning in the mammalian cochlear duct. Development 136:1977–1986

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto N, Chang W, Kelley MW (2011) Rbpj regulates development of prosensory cells in the mammalian inner ear. Dev Biol 353:367–379

    Article  PubMed  CAS  Google Scholar 

  • Yang H, Xie X, Deng M, Chen X, Gan L (2010a) Generation and characterization of Atoh1-Cre knock-in mouse line. Genesis 48:407–413

    Article  PubMed  CAS  Google Scholar 

  • Yang H, Gan J, Xie X, Deng M, Feng L, Chen X, Gao Z, Gan L (2010b) Gfi1-Cre knock-in mouse line: a tool for inner ear hair cell-specific gene deletion. Genesis 48:400–406

    Article  PubMed  CAS  Google Scholar 

  • Yoshida N, Hequembourg SJ, Atencio CA, Rosowski JJ, Liberman MC (2000) Acoustic injury in mice: 129/SvEv is exceptionally resistant to noise-induced hearing loss. Hear Res 141:97–106

    Article  PubMed  CAS  Google Scholar 

  • Young KM, Mitsumori T, Pringle N, Grist M, Kessaris N, Richardson WD (2010) An Fgfr3-iCreER(T2) transgenic mouse line for studies of neural stem cells and astrocytes. Glia 58:943–953

    PubMed  Google Scholar 

  • Yu Y, Zuo J (2009) The practical use of Cre and loxP technologies in mouse auditory research. Meth Mol Biol 493:87–102

    Article  CAS  Google Scholar 

  • Yu Y, Weber T, Yamashita T, Liu Z, Valentine MB, Cox BC, Zuo J (2010) In vivo proliferation of postmitotic cochlear supporting cells by acute ablation of the retinoblastoma protein in neonatal mice. J Neurosci 30:5927–5936

    Article  PubMed  CAS  Google Scholar 

  • Zambrowicz BP et al (2003) Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention. Proc Natl Acad Sci U S A 100:14109–14114

    Article  PubMed  Google Scholar 

  • Zelarayan LC, Vendrell V, Alvarez Y, Dominguez-Frutos E, Theil T, Alonso MT, Maconochie M, Schimmang T (2007) Differential requirements for FGF3, FGF8 and FGF10 during inner ear development. Dev Biol 308:379–391

    Article  PubMed  CAS  Google Scholar 

  • Zheng QY, Johnson KR, Erway LC (1999) Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 130:94–107

    Article  PubMed  CAS  Google Scholar 

  • Zheng B, Sage M, Sheppeard EA, Jurecic V, Bradley A (2000) Engineering mouse chromosomes with Cre-loxP: range, efficiency, and somatic applications. Mol Cell Biol 20:648–655

    Article  PubMed  CAS  Google Scholar 

  • Zhuo L, Theis M, Alvarez-Maya I, Brenner M, Willecke K, Messing A (2001) hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31:85–94

    Article  PubMed  CAS  Google Scholar 

  • Zuo J (2002) Transgenic and gene targeting studies of hair cell function in mouse inner ear. J Neurobiol 53:286–305

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Betsy Williford in the Biomedical Communications Department of St. Jude Children’s Research Hospital for her assistance in creating the artwork for figures. This work was supported in part by grants from the National Institute of Health (DC006471 (J.Z.), DC008800 (J.Z.), DC010310 (B.C.C.) and CA21765); the Office of Naval Research (N000140911014); the Sir Henry Wellcome Trust fellowship (M.M.M.L.); and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital. J. Zuo is a recipient of The Hartwell Individual Biomedical Research Award.

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  1. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Brandon C. Cox, Zhiyong Liu, Marcia M. Mellado Lagarde & Jian Zuo

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  1. Brandon C. Cox
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  2. Zhiyong Liu
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Correspondence to Jian Zuo.

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Cox, B.C., Liu, Z., Lagarde, M.M.M. et al. Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP . JARO 13, 295–322 (2012). https://doi.org/10.1007/s10162-012-0324-5

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