Suppressor of fused controls cerebellar neuronal differentiation in a manner modulated by GLI3 repressor and Fgf15

Dev Dyn. 2018 Jan;247(1):156-169. doi: 10.1002/dvdy.24526. Epub 2017 Jun 15.

Abstract

Background: Deficiency of Suppressor of Fused (SuFu), an intracellular mediator of Hedgehog signaling, in the murine mid-hindbrain disrupts cerebellar morphogenesis and cell differentiation in a manner that is rescued by constitutive expression of GLI3 transcriptional repressor (GLI3R). Here, we determined SuFu functions in cerebellar radial precursors following the stage of mid-hindbrain specification using a Blbp-Cre transgene.

Results: SuFu-deficient cerebella were severely dysplastic, and characterized by laminar disorganization, and delayed differentiation of ventricular zone-derived precursors. In vitro analysis of cerebellar precursors isolated from control and mutant mice demonstrated an increased proportion of radial glial precursors vs. Tuj1-positive neurons in mutant cultures. Abnormal cell differentiation in SuFu-deficient precursors was rescued by a constitutively expressed GLI3R knock-in allele, albeit with variable penetrance. Using RNA expression analysis in control and SuFu-deficient cerebellar anlage, we identified up-regulation of Fgf15 in mutant tissue. Strikingly, exogenous hFGF19, a mFGF15 ortholog, inhibited neuronal differentiation in cultures of wild-type cerebellar precursors. Moreover, siRNA-mediated knockdown of Fgf15 in SuFu-deficient cerebellar precursors rescued their delayed differentiation to neurons.

Conclusions: Together, our results show that SuFu promotes cerebellar radial precursor differentiation to neurons. SuFu function is mediated in part by GLI3R and down-regulation of Fgf15 expression. Developmental Dynamics 247:156-169, 2018. © 2017 Wiley Periodicals, Inc.

Keywords: SUFU-GLI regulation; cerebellar neurogenesis; radial glial differentiation; sonic hedgehog signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cerebellum / cytology
  • Cerebellum / metabolism*
  • Down-Regulation
  • Ependymoglial Cells / cytology
  • Ependymoglial Cells / metabolism
  • Fibroblast Growth Factors / metabolism*
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis / physiology
  • Neurons / cytology
  • Neurons / metabolism*
  • RNA, Small Interfering
  • Repressor Proteins / metabolism*
  • Signal Transduction / physiology
  • Zinc Finger Protein Gli3 / metabolism*

Substances

  • Gli3 protein, mouse
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • Sufu protein, mouse
  • Zinc Finger Protein Gli3
  • fibroblast growth factor 15, mouse
  • Fibroblast Growth Factors

Grant support