Skip to main content

Advertisement

SpringerLink
Log in

Shh-Mediated Increase in β-Catenin Levels Maintains Cerebellar Granule Neuron Progenitors in Proliferation

  • Original Paper
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

Cerebellar granule neuron progenitors (CGNPs) give rise to the cerebellar granule neurons in the developing cerebellum. Generation of large number of these neurons is made possible by the high proliferation rate of CGNPs in the external granule layer (EGL) in the dorsal cerebellum. Here, we show that upregulation of β-catenin can maintain murine CGNPs in a state of proliferation. Further, we show that β-catenin mRNA and protein levels can be regulated by the mitogen Sonic hedgehog (Shh). Shh signaling led to an increase in the level of the transcription factor N-myc. N-myc was found to bind the β-catenin promoter, and the increase in β-catenin mRNA and protein levels could be prevented by blocking N-myc upregulation downstream of Shh signaling. Furthermore, blocking Wingless-type MMTV integration site (Wnt) signaling by Wnt signaling pathway inhibitor Dickkopf 1 (Dkk-1) in the presence of Shh did not prevent the upregulation of β-catenin. We propose that in culture, Shh signaling regulates β-catenin expression through N-myc and results in increased CGNP proliferation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Miale IL, Sidman RL. An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol. 1961;4:277–96. https://doi.org/10.1016/0014-4886(61)90055-3.

    Article  CAS  PubMed  Google Scholar 

  2. Hatten ME. Neuronal regulation of astroglial morphology and proliferation in vitro. J Cell Biol. 1985;100:384–96. https://doi.org/10.1083/jcb.100.2.384.

    Article  CAS  PubMed  Google Scholar 

  3. Pons S, Trejo JL, Martinez-Morales JR, Marti E. Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation. Development. 2001;128:1481–92.

    CAS  PubMed  Google Scholar 

  4. Espinosa JS, Luo L. Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells. J Neurosci. 2008;28:2301–12. https://doi.org/10.1523/JNEUROSCI.5157-07.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fernandez C, Tatard VM, Bertrand N, Dahmane N. Differential modulation of Sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network. Dev Neurosci. 2010;32:59–70. https://doi.org/10.1159/000274458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roussel MF, Hatten ME. Cerebellum development and medulloblastoma. Curr Top Dev Biol. 2011;94:235–82. https://doi.org/10.1016/B978-0-12-380916-2.00008-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic hedgehog. Neuron. 1999;22:103–14. https://doi.org/10.1016/s0896-6273(00)80682-0.

    Article  CAS  PubMed  Google Scholar 

  8. Pogoriler J, Millen K, Utset M, Du W. Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation. Development. 2006;133:3929–37. https://doi.org/10.1242/dev.02556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kenney AM, Rowitch DH. Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol. 2000;20:9055–67. https://doi.org/10.1128/mcb.20.23.9055-9067.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002;16:2699–712. https://doi.org/10.1101/gad.1021202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kenney AM, Cole MD, Rowitch DH. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development. 2003;130:15–28. https://doi.org/10.1242/dev.00182.

    Article  CAS  PubMed  Google Scholar 

  12. Guldal CG, Ahmad A, Korshunov A, Squatrito M, Awan A, Mainwaring LA, et al. An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation. Acta Neuropathol. 2012;123:573–86. https://doi.org/10.1007/s00401-012-0946-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Eastman Q, Grosschedl R. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol. 1999;11:233–40. https://doi.org/10.1016/s0955-0674(99)80031-3.

    Article  CAS  PubMed  Google Scholar 

  14. Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. 2002;297:365–9. https://doi.org/10.1126/science.1074192.

    Article  CAS  PubMed  Google Scholar 

  15. Zechner D, Fujita Y, Hulsken J, Muller T, Walther I, Taketo MM, et al. beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol. 2003;258:406–18. https://doi.org/10.1016/s0012-1606(03)00123-4.

    Article  CAS  PubMed  Google Scholar 

  16. Woodhead GJ, Mutch CA, Olson EC, Chenn A. Cell-autonomous beta-catenin signaling regulates cortical precursor proliferation. J Neurosci. 2006;26:12620–30. https://doi.org/10.1523/JNEUROSCI.3180-06.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Herrera A, Saade M, Menendez A, Marti E, Pons S. Sustained Wnt/beta-catenin signalling causes neuroepithelial aberrations through the accumulation of aPKC at the apical pole. Nat Commun. 2014;5:4168. https://doi.org/10.1038/ncomms5168.

    Article  CAS  PubMed  Google Scholar 

  18. Draganova K, Zemke M, Zurkirchen L, Valenta T, Cantu C, Okoniewski M, et al. Wnt/beta-catenin signaling regulates sequential fate decisions of murine cortical precursor cells. Stem Cells. 2015;33:170–82. https://doi.org/10.1002/stem.1820.

    Article  CAS  PubMed  Google Scholar 

  19. Poschl J, Grammel D, Dorostkar MM, Kretzschmar HA, Schuller U. Constitutive activation of beta-catenin in neural progenitors results in disrupted proliferation and migration of neurons within the central nervous system. Dev Biol. 2013;374:319–32. https://doi.org/10.1016/j.ydbio.2012.12.001.

    Article  CAS  PubMed  Google Scholar 

  20. Selvadurai HJ, Mason JO. Wnt/beta-catenin signalling is active in a highly dynamic pattern during development of the mouse cerebellum. PLoS One. 2011;6:e23012. https://doi.org/10.1371/journal.pone.0023012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 1653;2003:1–24. https://doi.org/10.1016/s0304-419x(03)00005-2.

    Article  Google Scholar 

  22. Lorenz A, Deutschmann M, Ahlfeld J, Prix C, Koch A, Smits R, et al. Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors. Mol Cell Biol. 2011;31:3326–38. https://doi.org/10.1128/MCB.05718-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moreno N, Schmidt C, Ahlfeld J, Poschl J, Dittmar S, Pfister SM, et al. Loss of Smarc proteins impairs cerebellar development. J Neurosci. 2014;34:13486–91. https://doi.org/10.1523/JNEUROSCI.2560-14.2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schuller U, Rowitch DH. Beta-catenin function is required for cerebellar morphogenesis. Brain Res. 2007;1140:161–9. https://doi.org/10.1016/j.brainres.2006.05.105.

  25. Wen J, Yang HB, Zhou B, Lou HF, Duan S. beta-Catenin is critical for cerebellar foliation and lamination. PLoS One. 2013;8:e64451. https://doi.org/10.1371/journal.pone.0064451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010;468:1095–9. https://doi.org/10.1038/nature09587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Haldipur P, Sivaprakasam I, Periasamy V, Govindan S, Mani S. Asymmetric cell division of granule neuron progenitors in the external granule layer of the mouse cerebellum. Biol Open. 2015;4:865–72. https://doi.org/10.1242/bio.009886.

  28. Hutson TH, Buchser WJ, Bixby JL, Lemmon VP, Moon LD. Optimization of a 96-well electroporation assay for postnatal rat CNS neurons suitable for cost-effective medium-throughput screening of genes that promote Neurite outgrowth. Front Mol Neurosci. 2011;4:55. https://doi.org/10.3389/fnmol.2011.00055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13:767–79. https://doi.org/10.1038/nrm3470.

    Article  CAS  PubMed  Google Scholar 

  30. Anne SL, Govek EE, Ayrault O, Kim JH, Zhu X, Murphy DA, et al. WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PLoS One. 2013;8:e81769. https://doi.org/10.1371/journal.pone.0081769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, et al. The ground state of embryonic stem cell self-renewal. Nature. 2008;453:519–23. https://doi.org/10.1038/nature06968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rao AS, Kremenevskaja N, Resch J, Brabant G. Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling. Eur J Endocrinol. 2005;153:929–38. https://doi.org/10.1530/eje.1.02038.

    Article  CAS  PubMed  Google Scholar 

  33. Yang Y, Yang J, Liu R, Li H, Luo X, Yang G. Accumulation of beta-catenin by lithium chloride in porcine myoblast cultures accelerates cell differentiation. Mol Biol Rep. 2011;38:2043–9. https://doi.org/10.1007/s11033-010-0328-3.

    Article  CAS  PubMed  Google Scholar 

  34. Zeilbeck LF, Muller B, Knobloch V, Tamm ER, Ohlmann A. Differential angiogenic properties of lithium chloride in vitro and in vivo. PLoS One. 2014;9:e95546. https://doi.org/10.1371/journal.pone.0095546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fujita S. Quantitative analysis of cell proliferation and differentiation in the cortex of the postnatal mouse cerebellum. J Cell Biol. 1967;32:277–87. https://doi.org/10.1083/jcb.32.2.277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhi F, Gong G, Xu Y, Zhu Y, Hu D, Yang Y, et al. Activated beta-catenin forces N2A cell-derived neurons back to tumor-like neuroblasts and positively correlates with a risk for human neuroblastoma. Int J Biol Sci. 2012;8:289–97. https://doi.org/10.7150/ijbs.3520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lee HY, Greene LA, Mason CA, Manzini MC. Isolation and culture of post-natal mouse cerebellar granule neuron progenitor cells and neurons. J Vis Exp. 2009. https://doi.org/10.3791/990.

  38. Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31:2714–36. https://doi.org/10.1038/emboj.2012.150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dar MS, Singh P, Singh G, Jamwal G, Hussain SS, Rana A, et al. Terminal regions of beta-catenin are critical for regulating its adhesion and transcription functions. Biochim Biophys Acta. 1863;2016:2345–57. https://doi.org/10.1016/j.bbamcr.2016.06.010.

    Article  CAS  Google Scholar 

  40. Grigoryan T, Wend P, Klaus A, Birchmeier W. Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 2008;22:2308–41. https://doi.org/10.1101/gad.1686208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ye P, Xing Y, Dai Z, D'Ercole AJ. In vivo actions of insulin-like growth factor-I (IGF-I) on cerebellum development in transgenic mice: evidence that IGF-I increases proliferation of granule cell progenitors. Brain Res Dev Brain Res. 1996;95:44–54. https://doi.org/10.1016/0165-3806(96)00492-0.

    Article  CAS  PubMed  Google Scholar 

  42. Solecki DJ, Liu XL, Tomoda T, Fang Y, Hatten ME. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron. 2001;31:557–68. https://doi.org/10.1016/s0896-6273(01)00395-6.

    Article  CAS  PubMed  Google Scholar 

  43. Cui H, Meng Y, Bulleit RF. Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells. Brain Res Dev Brain Res. 1998;111:177–88. https://doi.org/10.1016/s0165-3806(98)00136-9.

    Article  CAS  PubMed  Google Scholar 

  44. Kenney AM, Widlund HR, Rowitch DH. Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors. Development. 2004;131:217–28. https://doi.org/10.1242/dev.00891.

    Article  CAS  PubMed  Google Scholar 

  45. Wallace VA. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999;9:445–8. https://doi.org/10.1016/s0960-9822(99)80195-x.

    Article  CAS  PubMed  Google Scholar 

  46. Corrales JD, Rocco GL, Blaess S, Guo Q, Joyner AL. Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development. Development. 2004;131:5581–90. https://doi.org/10.1242/dev.01438.

    Article  CAS  PubMed  Google Scholar 

  47. Hatton BA, Knoepfler PS, Kenney AM, Rowitch DH, de Alboran IM, Olson JM, et al. N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth. Cancer Res. 2006;66:8655–61. https://doi.org/10.1158/0008-5472.CAN-06-1621.

    Article  CAS  PubMed  Google Scholar 

  48. Li Q, Dashwood WM, Zhong X, Al-Fageeh M, Dashwood RH. Cloning of the rat beta-catenin gene (Ctnnb1) promoter and its functional analysis compared with the Catnb and CTNNB1 promoters. Genomics. 2004;83:231–42. https://doi.org/10.1016/j.ygeno.2003.08.004.

    Article  CAS  PubMed  Google Scholar 

  49. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics. 2005;21:2933–42. https://doi.org/10.1093/bioinformatics/bti473.

    Article  CAS  PubMed  Google Scholar 

  50. Sjostrom SK, Finn G, Hahn WC, Rowitch DH, Kenney AM. The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors. Dev Cell. 2005;9:327–38. https://doi.org/10.1016/j.devcel.2005.07.014.

    Article  CAS  PubMed  Google Scholar 

  51. Parathath SR, Mainwaring LA, Fernandez LA, Campbell DO, Kenney AM. Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors. Development. 2008;135:3291–300. https://doi.org/10.1242/dev.022871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Alvarez-Rodriguez R, Pons S. Expression of the proneural gene encoding Mash1 suppresses MYCN mitotic activity. J Cell Sci. 2009;122:595–9. https://doi.org/10.1242/jcs.037556.

    Article  CAS  PubMed  Google Scholar 

  53. Grammel D, Warmuth-Metz M, von Bueren AO, Kool M, Pietsch T, Kretzschmar HA, et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol. 2012;123:601–14. https://doi.org/10.1007/s00401-012-0961-0.

    Article  CAS  PubMed  Google Scholar 

  54. Matsuo S, Takahashi M, Inoue K, Tamura K, Irie K, Kodama Y, et al. Thickened area of external granular layer and Ki-67 positive focus are early events of medulloblastoma in Ptch1(+)/(−) mice. Exp Toxicol Pathol. 2013;65:863–73. https://doi.org/10.1016/j.etp.2012.12.005.

    Article  CAS  PubMed  Google Scholar 

  55. Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999;155:703–10. https://doi.org/10.1016/s0002-9440(10)65168-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kobayashi M, Honma T, Matsuda Y, Suzuki Y, Narisawa R, Ajioka Y, et al. Nuclear translocation of beta-catenin in colorectal cancer. Br J Cancer. 2000;82:1689–93. https://doi.org/10.1054/bjoc.1999.1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Xue J, Chen Y, Wu Y, Wang Z, Zhou A, Zhang S, et al. Tumour suppressor TRIM33 targets nuclear beta-catenin degradation. Nat Commun. 2015;6:6156. https://doi.org/10.1038/ncomms7156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pei Y, Brun SN, Markant SL, Lento W, Gibson P, Taketo MM, et al. WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum. Development. 2012;139:1724–33. https://doi.org/10.1242/dev.050104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hussein SM, Duff EK, Sirard C. Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. J Biol Chem. 2003;278:48805–14. https://doi.org/10.1074/jbc.M305472200.

    Article  CAS  PubMed  Google Scholar 

  60. Borycki AG, Brunk B, Tajbakhsh S, Buckingham M, Chiang C, Emerson CP Jr. Sonic hedgehog controls epaxial muscle determination through Myf5 activation. Development. 1999;126:4053–63.

    CAS  PubMed  Google Scholar 

  61. Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, et al. Transcriptional profiling of the sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci U S A. 2003;100:7331–6. https://doi.org/10.1073/pnas.0832317100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Browd SR, Kenney AM, Gottfried ON, Yoon JW, Walterhouse D, Pedone CA, et al. N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma. Cancer Res. 2006;66:2666–72. https://doi.org/10.1158/0008-5472.CAN-05-2198.

    Article  CAS  PubMed  Google Scholar 

  63. Kuwahara A, Hirabayashi Y, Knoepfler PS, Taketo MM, Sakai J, Kodama T, et al. Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex. Development. 2010;137:1035–44. https://doi.org/10.1242/dev.046417.

    Article  CAS  PubMed  Google Scholar 

  64. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106:1798–806. https://doi.org/10.1161/CIRCRESAHA.110.219840.

    Article  CAS  PubMed  Google Scholar 

  65. Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol. 2008;8:581–93. https://doi.org/10.1038/nri2360.

    Article  CAS  PubMed  Google Scholar 

  66. Tolwinski NS, Wehrli M, Rives A, Erdeniz N, DiNardo S, Wieschaus E. Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity. Dev Cell. 2003;4:407–18. https://doi.org/10.1016/s1534-5807(03)00063-7.

    Article  CAS  PubMed  Google Scholar 

  67. Rios I, Alvarez-Rodriguez R, Marti E, Pons S. Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development. 2004;131:3159–68. https://doi.org/10.1242/dev.01188.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Department of Science and Technology (Intensification of Research in High Priority Areas/IRPHA) and Neurobiology Task Force, Department of Biotechnology (DBTO-0376), Government of India. NR was supported by SwarnaJayanti Fellowship from the Department of Science and Technology, Government of India, and the DBT-IISc partnership program (BT/PR27952/INF/22/212/2018). The authors are grateful to Dr. Anindo Chatterjee for help with experiments, and to Dr. Deepak Saini (Indian Institute of Science, Bengaluru) and Dr. Sorab N. Dalal (ACTREC, Mumbai) for contributing plasmid constructs. The authors are thankful to the Central Animal Facility, Indian Institute of Science.

Author information

Author notes

  1. Shyamala Mani

    Present address: Université de Paris, Inserm UMR 1141 NeuroDiderot, F-75019, Paris, France

  2. Saranya Radhakrishnan and Rajit Narayanan Cheramangalam contributed equally to this work.

Authors and Affiliations

  1. Centre for Neuroscience, Indian Institute of Science, Bengaluru, 560012, India

    Shyamala Mani, Saranya Radhakrishnan, Rajit Narayanan Cheramangalam, Shalini Harkar, Samyutha Rajendran & Narendrakumar Ramanan

  2. Curadev Pharma, Pvt. Ltd., B-87, Sector 83, Noida, Uttar Pradesh, 201305, India

    Shyamala Mani

Authors
  1. Shyamala Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saranya Radhakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rajit Narayanan Cheramangalam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shalini Harkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samyutha Rajendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Narendrakumar Ramanan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shyamala Mani or Narendrakumar Ramanan.

Ethics declarations

Conflict of Interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 1206 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mani, S., Radhakrishnan, S., Cheramangalam, R.N. et al. Shh-Mediated Increase in β-Catenin Levels Maintains Cerebellar Granule Neuron Progenitors in Proliferation. Cerebellum 19, 645–664 (2020). https://doi.org/10.1007/s12311-020-01138-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-020-01138-2

Keywords

Search

Navigation