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Mtss1 promotes maturation and maintenance of cerebellar neurons via splice variant-specific effects

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Abstract

Efficient coupling of the actin cytoskeleton to the cell membrane is crucial for histogenesis and maintenance of the nervous system. At this critical interface, BAR (Bin–Amphiphysin–Rvs) proteins regulate membrane bending, shown to be instrumental for mobility and morphogenesis of individual cells. Yet, the systemic significance of these proteins remains largely unexplored. Here, we probe the role of a prominent member of this protein family, the inverse-BAR protein Mtss1, for the development and function of a paradigmatic neuronal circuit, the cerebellar cortex. Mtss1-null mice show granule cell ectopias, dysmorphic Purkinje cells, malformed axons, and a protracted neurodegeneration entailing age-dependent motor deficits. In postmitotic granule cells, which transiently express Mtss1 while they migrate and form neurites, Mtss1 impinges on directional persistence and neuritogenesis. The latter effect can be specifically attributed to its exon 12a splice variant. Targeted re-expression of Mtss1 in Mtss1-null animals indicated that these pathologies were largely due to cell type-specific and intrinsic effects. Together, our results provide a mechanistic perspective on Mtss1 function for brain development and degeneration and relate it to structural features of this protein.

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References

  • Altman J, Anderson WJ (1972) Experimental reorganization of the cerebellar cortex. I. Morphological effects of elimination of all microneurons with prolonged x-irradiation started at birth. J Comp Neurol 146:355–405

    Article  CAS  PubMed  Google Scholar 

  • Atwood SX, Li M, Lee A, Tang JY, Oro AE (2013) GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature 494:484–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baptista CA, Hatten ME, Blazeski R, Mason CA (1994) Cell-cell interactions influence survival and differentiation of purified Purkinje cells in vitro. Neuron 12:243–260

    Article  CAS  PubMed  Google Scholar 

  • Barlow CA, Laishram RS, Anderson RA (2010) Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum. Trends Cell Biol 20:25–35

    Article  CAS  PubMed  Google Scholar 

  • Barski JJ, Dethleffsen K, Meyer M (2000) Cre recombinase expression in cerebellar Purkinje cells. Genesis 28:93–98

    Article  CAS  PubMed  Google Scholar 

  • Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordatze PR, Guo Q, Matzuk MM, Zoghbi HY (1997) Math1 is essential for genesis of cerebellar granule neurons. Nature 390:169–172

    Article  CAS  PubMed  Google Scholar 

  • Bompard G, Sharp SJ, Freiss G, Machesky LM (2005) Involvement of Rac in actin cytoskeleton rearrangements induced by MIM-B. J Cell Sci 118:5393–5403

    Article  CAS  PubMed  Google Scholar 

  • Burov S, Jeon JH, Metzler R, Barkai E (2011) Single particle tracking in systems showing anomalous diffusion: the role of weak ergodicity breaking. Phys Chem Chem Phys 13:1800–1812

    Article  CAS  PubMed  Google Scholar 

  • Carlson BR, Lloyd KE, Kruszewski A, Kim IH, Rodriguiz RM, Heindel C, Faytell M, Dudek SM, Wetsel WC, Soderling SH (2011) WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory. J Neurosci 31:2447–2460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caviness VS Jr, Rakic P (1978) Mechanisms of cortical development: a view from mutations in mice. Annu Rev Neurosci 1:297–326

    Article  PubMed  Google Scholar 

  • Charrier C, Joshi K, Coutinho-Budd J, Kim JE, Lambert N, de MJ, Jin WL, Vanderhaeghen P, Ghosh A, Sassa T, Polleux F (2012) Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149:923–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crespo CL, Vernieri C, Keller PJ, Garre M, Bender JR, Wittbrodt J, Pardi R (2014) The PAR complex controls the spatiotemporal dynamics of F-actin and the MTOC in directionally migrating leukocytes. J Cell Sci 127:4381–4395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Da Silva JS, Dotti CG (2002) Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis. Nat Rev Neurosci 3:694–704

    Article  CAS  PubMed  Google Scholar 

  • Dawson JC, Bruche S, Spence HJ, Braga VM, Machesky LM (2012a) Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1. PLoS ONE 7:e31141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dawson JC, Timpson P, Kalna G, Machesky LM (2012b) Mtss1 regulates epidermal growth factor signaling in head and neck squamous carcinoma cells. Oncogene 31:1781–1793

    Article  CAS  PubMed  Google Scholar 

  • Dickinson RB, Tranquillo RT (1993) Optimal estimation of cell movement indices from the statistical analysis of cell tracking data. AIChE J 39:1995–2010.

    Article  Google Scholar 

  • Fernandez-Gonzalez A, La Spada AR, Treadaway J, Higdon JC, Harris BS, Sidman RL, Morgan JI, Zuo J (2002) Purkinje cell degeneration (pcd) phenotypes caused by mutations in the axotomy-induced gene, Nna1. Science 295:1904–1906

    Article  CAS  PubMed  Google Scholar 

  • Flynn KC (2013) The cytoskeleton and neurite initiation. Bioarchitecture 3:86–109

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao WQ, Heintz N, Hatten ME (1991) Cerebellar granule cell neurogenesis is regulated by cell-cell interactions in vitro. Neuron 6:705–715

    Article  CAS  PubMed  Google Scholar 

  • Glassmann A, Molly S, Surchev L, Nazwar TA, Holst M, Hartmann W, Baader SL, Oberdick J, Pietsch T, Schilling K (2007) Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells. BMC Dev Biol 7:111

    Article  PubMed  PubMed Central  Google Scholar 

  • Hayn-Leichsenring G, Liebig C, Miething A, Schulz A, Kumar S, Schwalbe M, Eiberger B, Baader SL (2011) Cellular distribution of metastasis suppressor 1 and the shape of cell bodies are temporarily altered in Engrailed-2 overexpressing cerebellar Purkinje cells. Neuroscience 189:68–78

    Article  CAS  PubMed  Google Scholar 

  • Hendzel MJ (2014) The F-act’s of nuclear actin. Curr Opin Cell Biol 28:84–89

    Article  CAS  PubMed  Google Scholar 

  • Hothorn T, Bretz F, Westfall P (2008) Simultaneous inference in general parametric models. Biom J 50:346–363

    Article  PubMed  Google Scholar 

  • Johnson MA, Sharma M, Mok MT, Henderson BR (2013) Stimulation of in vivo nuclear transport dynamics of actin and its co-factors IQGAP1 and Rac1 in response to DNA replication stress. Biochim Biophys Acta 1833:2334–2347

    Article  CAS  PubMed  Google Scholar 

  • Kim MH, Choi J, Yang J, Chung W, Kim JH, Paik SK, Kim K, Han S, Won H, Bae YS, Cho SH, Seo J, Bae YC, Choi SY, Kim E (2009) Enhanced NMDA receptor-mediated synaptic transmission, enhanced long-term potentiation, and impaired learning and memory in mice lacking IRSp53. J Neurosci 29:1586–1595

    Article  CAS  PubMed  Google Scholar 

  • Kullmann JA, Neumeyer A, Wickertsheim I, Bottcher RT, Costell M, Deitmer JW, Witke W, Friauf E, Rust MB (2012) Purkinje cell loss and motor coordination defects in profilin1 mutant mice. Neuroscience 223:355–364

    Article  CAS  PubMed  Google Scholar 

  • Lee YG, Macoska JA, Korenchuk S, Pienta KJ (2002) MIM, a potential metastasis suppressor gene in bladder cancer. Neoplasia 4:291–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lei R, Tang J, Zhuang X, Deng R, Li G, Yu J, Liang Y, Xiao J, Wang HY, Yang Q, Hu G (2014) Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis. Oncogene 33:1287–1296

    Article  CAS  PubMed  Google Scholar 

  • Leto K, Arancillo M, Becker EB, Buffo A, Chiang C, Ding B, Dobyns WB, Dusart I, Haldipur P, Hatten ME, Hoshino M, Joyner AL, Kano M, Kilpatrick DL, Koibuchi N, Marino S, Martinez S, Millen KJ, Millner TO, Miyata T, Parmigiani E, Schilling K, Sekerkova G, Sillitoe RV, Sotelo C, Uesaka N, Wefers A, Wingate RJ, Hawkes R (2016) Consensus paper: cerebellar development. Cerebellum 15:789–828

    Article  PubMed  Google Scholar 

  • Luo L, Hensch TK, Ackerman L, Barbel S, Jan LY, Jan YN (1996) Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature 379:837–840

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Manzano J, Cuadrado M, Morte B, Bernal J (2007) Influence of thyroid hormone and thyroid hormone receptors in the generation of cerebellar gamma-aminobutyric acid-ergic interneurons from precursor cells. Endocrinology 148:5746–5751

    Article  CAS  PubMed  Google Scholar 

  • Marin O, Rubenstein JL (2003) Cell migration in the forebrain. Annu Rev Neurosci 26:441–483

    Article  CAS  PubMed  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  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattila PK, Salminen M, Yamashiro T, Lappalainen P (2003) Mouse MIM, a tissue-specific regulator of cytoskeletal dynamics, interacts with ATP-actin monomers through its C-terminal WH2 domain. J Biol Chem 278:8452–8459

    Article  CAS  PubMed  Google Scholar 

  • Mattila PK, Pykalainen A, Saarikangas J, Paavilainen VO, Vihinen H, Jokitalo E, Lappalainen P (2007) Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism. J Cell Biol 176:953–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McClure C, Cole KL, Wulff P, Klugmann M, Murray AJ (2011) Production and titering of recombinant adeno-associated viral vectors. J Vis Expe 57:e3348

    Google Scholar 

  • Mertz KD, Pathria G, Wagner C, Saarikangas J, Sboner A, Romanov J, Gschaider M, Lenz F, Neumann F, Schreiner W, Nemethova M, Glassmann A, Lappalainen P, Stingl G, Small JV, Fink D, Chin L, Wagner SN (2014) MTSS1 is a metastasis driver in a subset of human melanomas. Nat Commun 5:3465

    Article  PubMed  Google Scholar 

  • Metin C, Vallee RB, Rakic P, Bhide PG (2008) Modes and mishaps of neuronal migration in the mammalian brain. J Neurosci 28:11746–11752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metzler R, Klafter J (2000) The random walk’s guide to anomalous diffusion: a fractional dynamics approach. Phys Rep 339:1–77.

    Article  CAS  Google Scholar 

  • Michalet X (2010) Mean square displacement analysis of single-particle trajectories with localization error: Brownian motion in an isotropic medium. Phys Rev E Stat Nonlin Soft Matter Phys 82:041914

    Article  PubMed  PubMed Central  Google Scholar 

  • Mulherkar S, Uddin MD, Couvillon AD, Sillitoe RV, Tolias KF (2014) The small GTPases RhoA and Rac1 regulate cerebellar development by controlling cell morphogenesis, migration and foliation. Dev Biol 394:39–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newman AJ, Tremblay A, Nichols ES, Neville HJ, Ullman MT (2011) The influence of language proficiency on lexical semantic processing in native and late learners of english. J Cogn Neurosci 24:1205–1223

    Article  PubMed  PubMed Central  Google Scholar 

  • Oberdick J, Smeyne RJ, Mann JR, Zackson S, Morgan JI (1990) A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 248:223–226

    Article  CAS  PubMed  Google Scholar 

  • Pan N, Jahan I, Lee JE, Fritzsch B (2009) Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg(Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation. Cell Tissue Res 337:407–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:2002–2007

    Article  Google Scholar 

  • R Core Team (2015) R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing ISBN 3-900051-07-0; http://www.R-project.org/.

  • Rakic P (1988) Specification of cerebral cortical areas. Science 241:170–176

    Article  CAS  PubMed  Google Scholar 

  • Ruthardt N, Lamb DC, Brauchle C (2011) Single-particle tracking as a quantitative microscopy-based approach to unravel cell entry mechanisms of viruses and pharmaceutical nanoparticles. Mol Ther 19:1199–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saarikangas J, Mattila PK, Varjosalo M, Bovellan M, Hakanen J, Calzada-Wack J, Tost M, Jennen L, Rathkolb B, Hans W, Horsch M, Hyvonen ME, Perala N, Fuchs H, Gailus-Durner V, Esposito I, Wolf E, De Angelis MH, Frilander MJ, Savilahti H, Sariola H, Sainio K, Lehtonen S, Taipale J, Salminen M, Lappalainen P (2011) Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia. J Cell Sci 124:1245–1255

    Article  CAS  PubMed  Google Scholar 

  • Saarikangas J, Kourdougli N, Senju Y, Chazal G, Segerstrale M, Minkeviciene R, Kuurne J, Mattila PK, Garrett L, Holter SM, Becker L, Racz I, Hans W, Klopstock T, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de AM, von OL, Taira T, Lappalainen P, Rivera C, Hotulainen P (2015) MIM-induced membrane bending promotes dendritic spine initiation. Dev Cell 33:644–659

    Article  CAS  PubMed  Google Scholar 

  • Sawallisch C, Berhorster K, Disanza A, Mantoani S, Kintscher M, Stoenica L, Dityatev A, Sieber S, Kindler S, Morellini F, Schweizer M, Boeckers TM, Korte M, Scita G, Kreienkamp HJ (2009) The insulin receptor substrate of 53 kDa (IRSp53) limits hippocampal synaptic plasticity. J Biol Chem 284:9225–9236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schilling K, Dickinson MH, Connor JA, Morgan JI (1991a) Electrical activity in cerebellar cultures determines Purkinje cell dendritic growth patterns. Neuron 7:891–902

    Article  CAS  PubMed  Google Scholar 

  • Schilling K, Luk D, Curran T, Morgan JI (1991b) Regulation of a fos-lacZ fusion gene: a paradigm for quantitative analysis of stimulus-transcription coupling. Proc Natl Acad Sci USA 88:5665–5669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solecki DJ, Model L, Gaetz J, Kapoor TM, Hatten ME (2004) Par6alpha signaling controls glial-guided neuronal migration. Nat Neurosci 7:1195–1203

    Article  CAS  PubMed  Google Scholar 

  • Sotelo C, Rossi F (2013) Purkinje cell migration and differentiation. In: Manto M, Gruol DL, Schmahmann JD, Koibuchi N, Rossi F (eds) Handbook of the cerebellum and cerebellar disorders. Springer, New York, pp 147–178

    Chapter  Google Scholar 

  • Suetsugu S (2010) The proposed functions of membrane curvatures mediated by the BAR domain superfamily proteins. J Biochem 148:1–12

    Article  CAS  PubMed  Google Scholar 

  • Suetsugu S, Murayama K, Sakamoto A, Hanawa-Suetsugu K, Seto A, Oikawa T, Mishima C, Shirouzu M, Takenawa T, Yokoyama S (2006) The RAC binding domain/IRSp53-MIM homology domain of IRSp53 induces RAC-dependent membrane deformation. J Biol Chem 281:35347–35358

    Article  CAS  PubMed  Google Scholar 

  • Suetsugu S, Kurisu S, Takenawa T (2014) Dynamic shaping of cellular membranes by phospholipids and membrane-deforming proteins. Physiol Rev 94:1219–1248

    Article  CAS  PubMed  Google Scholar 

  • Tabata T, Sawada S, Araki K, Bono Y, Furuya S, Kano M (2000) A reliable method for culture of dissociated mouse cerebellar cells enriched for Purkinje neurons. J Neurosci Methods 104:45–53

    Article  CAS  PubMed  Google Scholar 

  • Tahirovic S, Hellal F, Neukirchen D, Hindges R, Garvalov BK, Flynn KC, Stradal TE, Chrostek-Grashoff A, Brakebusch C, Bradke F (2010) Rac1 regulates neuronal polarization through the WAVE complex. J Neurosci 30:6930–6943

    Article  CAS  PubMed  Google Scholar 

  • Tarnok K, Czirok A, Czondor K, Schlett K (2005) Cerebellar granule cells show age-dependent migratory differences in vitro. J Neurobiol 65:135–145

    Article  CAS  PubMed  Google Scholar 

  • Treisman R (2013) Shedding light on nuclear actin dynamics and function. Trends Biochem Sci 38:376–377

    Article  CAS  PubMed  Google Scholar 

  • Trenkner E, Smith D, Segil N (1984) Is cerebellar granule cell migration regulated by an internal clock? J Neurosci 4:2850–2855

    CAS  PubMed  Google Scholar 

  • Van Dine SE, Siu NY, Toia A, Cuoco JA, Betz AJ, Bolivar VJ, Torres G, Ramos RL (2015) Spontaneous malformations of the cerebellar vermis: Prevalence, inheritance, and relationship to lobule/fissure organization in the C57BL/6 lineage. Neuroscience 310:242–251

    Article  PubMed  Google Scholar 

  • Vilz TO, Moepps B, Engele J, Molly S, Littman DR, Schilling K (2005) The SDF-1/CXCR4 pathway and the development of the cerebellar system. Eur J Neurosci 22:1831–1839

    Article  PubMed  Google Scholar 

  • Weyer A, Schilling K (2003) Developmental and cell type-specific expression of the neuronal marker NeuN in the murine cerebellum. J Neurosci Res 73:400–409

    Article  CAS  PubMed  Google Scholar 

  • Xia S, Li X, Johnson T, Seidel C, Wallace DP, Li R (2010) Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts. Development 137:1075–1084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhan T, Cao C, Li L, Gu N, Civin CI, Zhan X (2016) MIM regulates the trafficking of bone marrow cells via modulating surface expression of CXCR4. Leukemia 30:1327–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully acknowledge the generous gift of Mtss1-deficient animals by Dr. Rong Li; of Atoh1-cre animals by Dr. Ulrich Schüller and Pcp2-cre mice by Dr. Michael Meyer. We are greatly indebted to Andrea Christ and Helma Langmann for excellent technical assistance, Daniela Krauss and Narziss Haias for invaluable help with animal husbandry; Alexander Glassmann and Kirsten Knapp for providing plasmids containing Mtss1-cDNA, and to Benjamin Odermatt for many constructive discussions.

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  1. Anatomisches Institut, Anatomie and Zellbiologie, University of Bonn, Nussallee 10, 53115, Bonn, Germany

    Thorsten Sistig, Fanziska Lang, Sebastian Wrobel, Stephan L. Baader, Karl Schilling & Britta Eiberger

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  1. Thorsten Sistig
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  2. Fanziska Lang
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  3. Sebastian Wrobel
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  4. Stephan L. Baader
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Correspondence to Britta Eiberger.

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Additional information

While this manuscript was under review, Yu et al. (Neuroscience, (2016) 333:123–131; doi: http://dx.doi.org/10.1016/j.neuroscience.2016.07.002) described differential effects of Mtss1 on axonal and dendritic growth in cultured granule cells that are fully consistent with our in vivo and in vitro observations.

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Sistig, T., Lang, F., Wrobel, S. et al. Mtss1 promotes maturation and maintenance of cerebellar neurons via splice variant-specific effects. Brain Struct Funct 222, 2787–2805 (2017). https://doi.org/10.1007/s00429-017-1372-8

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