MicroRNAs Promote Granule Cell Expansion in the Cerebellum Through Gli2

  • Constantin L
  • Wainwright B
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Abstract

MicroRNAs (miRNAs) are important regulators of cerebellar function and homeostasis. Their deregulation re-sults in cerebellar neuronal degeneration and spinocerebellar ataxia type 1 and contributes to medulloblastoma. Canonical miRNA processing involves Dicer, which cleaves precursor miRNAs into mature double-stranded RNA duplexes. In order to address the role of miRNAs in cerebellar granule cell pre-cursor development, loxP-flanked exons of Dicer1 were con-ditionally inactivated using the granule cell precursor-specific Atoh1-Cre recombinase. A reduction of 87 % in Dicer1 tran-script was achieved in this conditional Dicer knockdown mod-el. Although knockdown resulted in normal survival, mice had disruptions to the cortical layering of the anterior cerebel-lum, which resulted from the premature differentiation of granule cell precursors in this region during neonatal develop-ment. This defect manifested as a thinner external granular layer with ectopic mature granule cells, and a depleted internal granular layer. We found that expression of the activator com-ponents of the Hedgehog-Patched pathway, the Gli family of transcription factors, was perturbed in conditional Dicer knockdown mice. We propose that loss of Gli2 mRNA medi-ated the anterior-restricted defect in conditional Dicer knock-down mice and, as proof of principle, were able to show that miR-106b positively regulated Gli2 mRNA expression. These findings confirm the importance of miRNAs as positive me-diators of Hedgehog-Patched signalling during granule cell precursor development.

Author-supplied keywords

  • Cerebellum
  • Dicer1 protein
  • Gli2 protein
  • Growth and development
  • Mirn106 microRNA
  • Mouse

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