Abstract
Gas1 is a pleiotropic protein that inhibits cell growth when overexpressed in tumors but during development, it acts as a co-receptor for sonic hedgehog to promote the proliferation and survival of various growing organs and systems. This protein has been extensively studied during development in the cerebellum. However, in other structures of the central nervous system, information concerning Gas1 is limited to in situ hybridization studies. We investigate the pattern of Gas1 expression during various developmental stages of the cortex and dentate gyrus of the mouse brain. The levels of Gas1 decrease in the developing brain and the protein is mainly found in progenitor cells during the development of the cortex and dentate gyrus.
Similar content being viewed by others
References
Agostini M, Tucci P, Killick R, Rouleau M, Candi E, Sayan BS, Cervo PR di val, Pierluigi N, McKeon F, Knight RA, Mak TW, Melino G (2011a) Neuronal differentiation by Tap73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci U S A 108:21093–21098
Agostini M, Tucci P, Steinert JR, Shalom-Feuerstein R, Rouleau M, Aberdam D, Forsythe ID, Young KW, Ventura A, Concepcion CP, Han Y, Candi E, Knight RA, Mak TW, Melino G (2011b) MicroRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proc Natl Acad Sci U S A 108:21099–21104
Allen BL, Song JY, Izzi L, Althaus IW, Kang JS, Charron F, Krauss RS, McMahon AP (2011) Overlapping roles and collective requirement for the coreceptors GAS1, CDO and BOC in SHH pathway function. Dev Cell 20:775–787
Altman J, Bayer SA (1990a) Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 301:365–381
Altman J, Bayer SA (1990b) Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J Comp Neurol 301:325–342
Aranha MM, Santos DM, Solá S, Steer CJ, Rodrigues CMP (2011) MiR-34a regulates mouse neural stem cell differentiation. PLoS One 6:e21396
Ayala-Sarmiento AE, Martinez-Fong D, Segovia J (2015) The internalization of neurotensin by the low-affinity neurotensin receptors (NTSR2 and vNTSR2) activates ERK 1/2 in glioma cells and allows neurotensin-polyplex transfection of tGAS1. Cell Mol Neurobiol 35:785–795
Benitez JA, Arregui L, Vergara P, Segovia J (2007) Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas. Cancer Gene Ther 14:836–846
Biau S, Shiying J, Chen-Ming F (2013) Gastrointestinal defects of the Gas1 mutant involve dysregulated hedgehog and ret signaling. Biol Open 2:144–155
Bommer G, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, MacDougald OA, Cho KR, Fearon ER (2007) P53-mediated activation of miRNA 34 candidate tumor-suppressor genes. Curr Biol 17:1298–1307
Bonaguidi MA, Song J, Ming G, Song H (2012) A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus. Curr Opin Neurobiol 22:754–761
Charytoniuk D, Porcel B, Rodriguez-Gomez J, Faure H, Ruat M, Traiffort E (2002) Sonic hedgehog signaling in the developing and adult brain. J Physiol (Paris) 96:9–16
Choi-Lundberg DL, Bohn MC (1995) Ontogeny and distribution of glial cell line-derived neurotrophic factor (GDNF) mRNA in rat. Dev Brain Res 85:80–88
Del Sal DG, Ruaro ME, Philipson L, Schneider C (1992) The growth arrest-specific gene, Gas1, is involved in growth suppression. Cell 70:595–607
Domínguez-Monzón G, Benítez JA, Vergara P, Lorenzana R, Segovia J (2009) Gas1 inhibits cell proliferation and induces apoptosis of human primary gliomas in the absence of Shh. Int J Dev Neurosci 27:305–313
Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, Kreidberg J, Anton ES (2000) Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron 27:33–44
Evdokiou A, Cowled PA (1998) Growth-regulatory activity of the growth arrest-specific gene, Gas1 in the NIH3T3 fibroblasts. Exp Cell Res 240:359–367
Evsyukova I, Plestant C, Anton ES (2013) Integrative mechanisms of oriented neuronal migration in the developing brain. Annu Rev Cell Dev Biol 29:299–353
Fineberg SK, Datta P, Stein CS, Davidson B (2012) MiR-34a represses numbl in murine neural progenitor cells and antagonizes neuronal differentiation. PLoS One 7:e38562
Garcia-Tovar CG, Perez A, Luna J, Mena R, Osorio B, Aleman V, Mondragon R, Mornet D, Rendon A, Hernandez JM (2001) Biochemical and histochemical analysis of 71 kDa dystrophin isoform (Dp71f) in rat brain. Acta Histochem 103:209–224
Götz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6:777–788
Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider-Maunoury S, Alvarez-Buylla A (2008) Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11:277–284
Haubensak W, Attardo A, Denk W, Huttner WB (2004) Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proc Natl Acad Sci U S A 101:3196–3201
Hodge RD, García AJ III, Elsen GE, Nelson BR, Mussar KE, Reiner SL, Ramírez JM, Hevner RF (2013) Tbr2 expression in Cajal-Retzius cells and intermediate neuronal progenitors is required for morphogenesis of the dentate gyrus. J Neurosci 33:4165–4112
Hsu Y, Li L, Fuchs E (2014) Transit amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157:935–949
Hutton SR, Pevny LH (2011) Sox2 expression levels distinguish between neural progenitor populations of the developing dorsal telencephalon. Dev Biol 352:40–47
Izzi L, Lévesque M, Morin S, Laniel D, Wilkes B, Mille F, Krauss R, McMahon A, Allen B, Charron F (2011) Boc and Gas1 each form distinct Shh receptor complexes with Ptch and are required for Shh-mediated cell proliferation. Dev Cell 20:788–801
Jiménez A, López-Ornelas A, Estudillo E, González-Mariscal L, González RO, Segovia J (2014) A soluble form of GAS1 inhibits tumor growth and angiogenesis in a triple negative breast cancer model. Exp Cell Res 327:307–317
Kann M, Bae E, Lenz MO, Li L, Trannguyen B, Schumacher VA, Taglienti ME, Bordeianou L, Hartwig S, Rinschen MM, Schermer B, Benzing T, Fan CM, Kreidberg JA (2015) WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals. Development 142:1254–1266
Kriegstein A, Álvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184
Lai K, Kaspar BK, Gage FH, Schaffer DV (2003) Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6:21–27
Lee CS, Fan CM (2001) Embryonic expression patterns of the mouse and chick Gas1 genes. Mech Dev 101:293–297
Lee SW, Clemenson GD, Gage FH (2012) New neurons in an aged brain. Behav Brain Res 227:497–507
Li G, Pleasure S (2005) Morphogenesis of the dentate gyrus: what we are learning from mouse mutants. Dev Neurosci 27:93–99
Li G, Fang L, Fernández G, Pleasure S (2013) The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron 78:658–672
Li G, Kataoka H, Coughlin SR, Pleasure SJ (2009) Identification of a transient subpial neurogenic zone in the developing dentate gyrus and its regulation by Cxcl12 and reelin signaling. Development 136:327–335
Liu Y, May NR, Fan CM (2001) Growth arrest specific 1 gene is a positive growth regulator for the cerebellum. Dev Biol 236:30–45
Liscovitch N, Chechik G (2013) Specialization of gene expression during mouse brain development. Plos One 9:e1003185
López-Ornelas A, Mejía-Castillo T, Vergara P, Segovia J (2011) Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth. Cancer Gene Ther 18:87–99
López-Ornelas A, Vergara P, Segovia J (2014) Neural stem cells producing an inducible and soluble form of GAS1 target and inhibit intracranial glioma growth. Cytotherapy 16:1011–1023
Loulier K, Lathia JD, Marthiens V, Relucio J, Mughal MR, Tang S, Coksaygan T, Hall PE, Chigurupati S, Patton B, Colognato H, Rao MS, Mattson MP, Haydar TF, ffrench-Constant C (2009) β1 Integrin maintains integrity of the embryonic neocortical stem cell niche. PLoS Biol 7:e1000176
Ma Y, Qin H, Cui Y (2013) MiR-34a targets GAS1 to promote cell proliferation and inhibits apoptosis in papillary thyroid carcicoma via PI3K/Akt/Bad pathway. Biochem Biophys Res Commun 441:958–963
Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S (2003) Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39:937
Martinelli DC, Fan CM (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21:1231–1243
Mathew E, Zhang Y, Holtz A, Kane K, Song J, Allen B, Pasca di Magliano M (2014) Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling. Cell Rep 9:1–11
Mathews EA, Morgenstern NA, Piatti VC, Zhao C, Jessberger S, Schinder AF, Gage FH (2010) A distinctive layering pattern of mouse dentate granule cells is generated by developmental and adult neurogenesis. J Comp Neurol 518:4479–4490
Morgado A, Xavier J, Dionísio PA, Ribeiro MFC, Dias R, Sebastiao AM, Solá S, Rodrigues CMP (2014) MicroRNA-34a modulates neural stem cell differentiation by regulating expression of synaptic and authophagic proteins. Mol Neurobiol 51:1168–1183
Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases.Nat Neurosci 7:136–144
Obayashi S, Tabunoki H, Kim SU, Satoh J (2009) Gene expression profiling of human neural progenitor cells following the serum-induced astrocyte differentiation. Cell Mol Neurobiol 29:423–438
Paratcha G, Ledda F, Baars L, Coulpier M, Besset V, Anders J, Scott R, Ibáñez CF (2001) Released GFRa1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Cell 29:171–184
Petrova R, Joyner AL (2014) Roles of sonic hedgehog signaling in adult organ homeostasis and repair. Development 141:3445–3457
Pleasure SJ, Collins AE, Lowenstein DH (2000) Unique expression patterns of cell fate molecules delineate sequential stages of dentate gyrus development. J Neurosci 20:6095–6105
Remboutsika E, Elkouris M, Iulianella A, Andoniadou C, Poulou M, Mitsiadis T, Trainor P, Lovell-Badge R (2011) Flexibility of neural stem cells. Front Physiol 2:16
Roeyen CR van, Zok S, Pruessmeyer J, Boor P, Nagayama Y, Fleckestein S, Cohen CD, Eitner F, Gröne HJ, Ostendorf T, Ludwig A, Floege J (2013) Growth arrest specific 1 is a novel endogenous inhibitor of glomerular cell activation and proliferation. Kidney Int 83:251–263
Rogers K, Schier A (2011) Morphogen gradients: from generation to interpretation. Annu Rev Cell Dev Biol 27:377–407
Ruat M, Roudaut H, Ferent J, Traiffort E (2012) Hedgehog trafficking cilia and brain functions. Differentiation 83:97–104
Schneider C, King RM, Philipson L (1988) Genes specifically expressed at growth arrest of mammalians cells. Cell 54:787–793
Schueler-Furman O, Glick E, Segovia J, Linial M (2006) Is GAS1 a co-receptor for the GDNF family of ligands? Trends Pharmacol Sci 27:72–77
Seppala M, Depew MJ, Martinelli DC, Fan CM, Sharpe PT, Cobourne MT (2007) Gas1 is a modifier of holopresencephaly and genetically interacts with sonic hedgehog. J Clin Invest 117:1575–1584
Seppala M, Xavier GM, Fan CM, Cobourne MT (2014) Boc modifies the spectrum of holoprosencephaly in the absence of Gas1 function. Biol Open 3:728–740
Seri B, García-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A (2004) Cell types, lineage and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 478:359–378
Stebel M, Vatta P, Ruaro ME, Del Sal G, Parton RG, Schneider C (2000) The growth suppressing Gas1 product is a GPI-linked protein. FEBS Lett 481:152–158
Steiner B, Klempin F, Wang L, Kott M, Kettenmann H, Kempermann G (2006) Type-2 cells as link between glial and neuronal linage in adult hippocampal neurogenesis. Glia 54:805–814
Sugiyama T, Osumi N, Katsuyama Y (2013) The germinal matrices in the developing dentate gyrus are composed of neuronal progenitors at distinct differentiation stage. Dev Dyn 242:1442–1453
Suh H, Consiglio A, Ray J, Sawai T, D’Amour KA, Gage FH (2007) In vivo fate analysis reveals the multipotent self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell 1:515–528
TuckerES, PolleuxF, LaMantiaA-S (2006) Position and time specify the migration of a pioneering population ofolfactory bulb interneurons. Dev Biol 297:387–401
Yan D, Wu Y, Yang Y, Belenkaya T, Tang X, Lin X (2010) The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development. Development 137:2033–2044
Zamorano A, Lamas M, Vergara P, Naranjo JR, Segovia J (2003) Transcriptionally mediated gene targeting of Gas1 to glioma cells elicits growth arrest and apoptosis. J Neurosci Res 71:256–263
Zarco N, González-Ramírez R, González RO, Segovia J (2012) GAS1 induces cell death through an intrinsic apoptotic pathway. Apoptosis 6:627–635
Zarco N, Bautista E, Cuéllar M, Vergara P, Flores-Rodríguez P, Aguilar-Roblero R, Segovia J (2013) Growth arrest specific 1 (GAS1) is abundantly expressed in the adult mouse central nervous system. J Histochem Cytochem 61:731–748
Acknowledgments
We thank Dr. J. Hernández (Cinvestav) for the kind gift of the β-actin antibody and R. Sánchez for technical support.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was partially supported by Conacyt grant 127357 (JS).
Electronic supplementary material
Below is the link to the electronic supplementary material.
Fig. S1
NIH3T3 cells in serum starved and proliferating conditions. Gas1 (red) is present in high concentrations only in starving NIH3T3 cells. (GIF 43 kb)
Fig. S2
Immunofluorescence against Gas1 in lung (a) and heart (b) (GIF 139 kb)
Fig. S3
Pulse-chase assay during the development of the dentate gyrus: 2 days after BrdU uptake (E16.5). a Panoramic view of a DG of an E16.5 embryo that received BrdU at E14.5. b-e A Gas1/BrdU positive cell at the DMS (arrow) from the inset in a; c-e are magnifications from b. f-i A Gas1/BrdU positive cell at the DG (arrow) from the inset in a; g-i are magnifications from f. DMS dentate migratory stream; DG dentate gyrus. a Scale bar 100 μm; b scale bar 20 μm; c and d scale bars 5 μm; f scale bar 20 μm; g and h scale bar 5 μm. (GIF 491 kb)
Fig. S4
Pulse-chase assay during the development of the dentate gyrus: images of a newborn mouse after BrdU uptake at E14.5. a Panoramic view of a DG from a newborn mouse. b-e A Gas1/BrdU positive cell at the dentate gyrus (arrow) along with a BrdU positive cell that lacks of Gas1 (asterisk); c-e are magnifications from b. a Scale bar 100 μm; b scale bar 50 μm; c-d scale bar 10 μm. (GIF 268 kb)
Fig. S5
Immunofluorescence of Gas1 and β-tubulin class III in the cortex of an E14.5 embryo. c-d Magnifications from the highest inset in b; e magnification from d; f orthogonal section from e; h orthogonal section from g; i magnification from g; j orthogonal section from i; k magnification from the nearest inset to the LV in b; l orthogonal section from k. LV lateral ventricle; CP cortical plate. a-b Scale bar 100 μm; c-d scale bar 20 μm; scale bar 10 μm in e; scale bar 10 μm in g; scale bar 10 μm in i; scale bar 20 μm in k. (GIF 214 kb)
Fig. S6
Immunofluorescence of Gas1 and β-tubulin class III in the cortex of E15.5 embryo. b is a magnification from a; c orthogonal section from b. LV lateral ventricle; CP cortical plate. Scale bar 100 μm in a; scale bar 20 μm in b. (GIF 150 kb)
Fig. S7
Immunofluorescence of Gas1 and Gfap expressing cells in the dentate gyrus of newborn mice. b Magnification from the inset in a; c a Gfap/Gas1 positive cell from the inset of b; d orthogonal section from c. Scale bar 100 μm in a; scale bar 20 μm in b; scale bar 5 μm in c. (GIF 333 kb)
Rights and permissions
About this article
Cite this article
Estudillo, E., Zavala, P., Pérez-Sánchez, G. et al. Gas1 is present in germinal niches of developing dentate gyrus and cortex. Cell Tissue Res 364, 369–384 (2016). https://doi.org/10.1007/s00441-015-2338-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-015-2338-x