Suppressor of fused controls cerebellar neuronal differentiation in a manner modulated by GLI3 repressor and Fgf15.
Dev Dyn
; 247(1): 156-169, 2018 01.
Article
en En
| MEDLINE
| ID: mdl-28560839
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 247156-169, 2018. © 2017 Wiley Periodicals, Inc.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
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Diferenciación Celular
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Cerebelo
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Factores de Crecimiento de Fibroblastos
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Proteína Gli3 con Dedos de Zinc
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Proteínas del Tejido Nervioso
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2018
Tipo del documento:
Article