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Suppressor of fused controls cerebellar neuronal differentiation in a manner modulated by GLI3 repressor and Fgf15
Author(s) -
Kim Jinny J.,
Jiwani Tayyaba,
Erwood Steven,
Loree Jillian,
Rosenblum Norman D.
Publication year - 2018
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.24526
Subject(s) - biology , cerebellum , microbiology and biotechnology , mutant , repressor , cellular differentiation , gli3 , gene knockdown , hindbrain , transcription factor , genetics , cell culture , gene , endocrinology , embryo
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.