Irina Sedykh1,2,3, Abigail N Keller1,2, Baul Yoon1,2,4, Laura Roberson1,2, Oleg V Moskvin5, Yevgenya Grinblat1,2,6. 1. Department of Integrative Biology, University of Wisconsin, Madison, Wisconsin. 2. Department of Neuroscience, University of Wisconsin, Madison, Wisconsin. 3. Zoology Ph.D. Program, University of Wisconsin, Madison, Wisconsin. 4. Genetics Ph.D. Training Program, University of Wisconsin, Madison, Wisconsin. 5. Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin. 6. McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin.
Abstract
BACKGROUND: Rfx winged-helix transcription factors, best known as key regulators of core ciliogenesis, also play ciliogenesis-independent roles during neural development. Mammalian Rfx4 controls neural tube morphogenesis via both mechanisms. RESULTS: We set out to identify conserved aspects of rfx4 gene function during vertebrate development and to establish a new genetic model in which to analyze these mechanisms further. To this end, we have generated frame-shift alleles in the zebrafish rfx4 locus using CRISPR/Cas9 mutagenesis. Using RNAseq-based transcriptome analysis, in situ hybridization and immunostaining we identified a requirement for zebrafish rfx4 in the forming midlines of the caudal neural tube. These functions are mediated, least in part, through transcriptional regulation of several zic genes in the dorsal hindbrain and of foxa2 in the ventral hindbrain and spinal cord (floor plate). CONCLUSIONS: The midline patterning functions of rfx4 are conserved, because rfx4 regulates transcription of foxa2 and zic2 in zebrafish and in mouse. In contrast, zebrafish rfx4 function is dispensable for forebrain morphogenesis, while mouse rfx4 is required for normal formation of forebrain ventricles in a ciliogenesis-dependent manner. Collectively, this report identifies conserved aspects of rfx4 function and establishes a robust new genetic model for in-depth dissection of these mechanisms. Developmental Dynamics 247:650-659, 2018.
BACKGROUND: Rfx winged-helix transcription factors, best known as key regulators of core ciliogenesis, also play ciliogenesis-independent roles during neural development. MammalianRfx4 controls neural tube morphogenesis via both mechanisms. RESULTS: We set out to identify conserved aspects of rfx4 gene function during vertebrate development and to establish a new genetic model in which to analyze these mechanisms further. To this end, we have generated frame-shift alleles in the zebrafishrfx4 locus using CRISPR/Cas9 mutagenesis. Using RNAseq-based transcriptome analysis, in situ hybridization and immunostaining we identified a requirement for zebrafishrfx4 in the forming midlines of the caudal neural tube. These functions are mediated, least in part, through transcriptional regulation of several zic genes in the dorsal hindbrain and of foxa2 in the ventral hindbrain and spinal cord (floor plate). CONCLUSIONS: The midline patterning functions of rfx4 are conserved, because rfx4 regulates transcription of foxa2 and zic2 in zebrafish and in mouse. In contrast, zebrafishrfx4 function is dispensable for forebrain morphogenesis, while mouserfx4 is required for normal formation of forebrain ventricles in a ciliogenesis-dependent manner. Collectively, this report identifies conserved aspects of rfx4 function and establishes a robust new genetic model for in-depth dissection of these mechanisms. Developmental Dynamics 247:650-659, 2018.
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