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

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.

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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.

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Correspondence to Shyamala Mani or Narendrakumar Ramanan.

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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

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Keywords

  • Sonic hedgehog
  • Cerebellar granule neuron progenitors
  • β-Catenin
  • N-myc