title: Mutual antagonism of the paired-type homeobox genes, vsx2 and dmbx1, regulates retinal progenitor cell cycle exit upstream of ccnd1 expression.
abstract: Understanding the mechanisms that regulate the transition between the proliferative and a post-mitotic state of retinal progenitor cells (RPCs) is key to advancing our knowledge of retinal growth and maturation. In the present study we determined that during zebrafish embryonic retinal neurogenesis, two paired-type homeobox genes - vsx2 and dmbx1 - function in a mutually antagonistic manner. We demonstrate that vsx2 gene expression requires active Fgf signaling and that this in turn suppresses dmbx1 expression and maintains cells in an undifferentiated, proliferative RPC state. This vsx2-dependent RPC state can be prolonged cell-autonomously by knockdown of dmbx1, or it can be suppressed prematurely by the over-expression of dmbx1, which we show can inhibit vsx2 expression and lead to precocious neuronal differentiation. dmbx1 loss of function also results in altered expression of canonical cell cycle genes, and in particular up-regulation of ccnd1, which correlates with our previous finding of a prolonged RPC cell cycle. By knocking down ccnd1 and dmbx1 simultaneously, we show that RPCs can overcome this phenotype to exit the cell cycle on time and differentiate normally into retinal neurons. Collectively, our data provide novel insight into the mechanism that enables RPCs to exit the cell cycle through a previously unrecognized antagonistic interaction of two paired-type homeobox genes that are central regulators of an Fgf-vsx2-dmbx1-ccnd1 signaling axis.
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
authors: Loksum
authors: L
authors: Wong
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
authors: Namita
authors: N
authors: Power
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
authors: Amanda
authors: A
authors: Miles
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada M5T 3A9; Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario, Canada M5S 3B2. Electronic address: v.tropepe@utoronto.ca.
authors: Vincent
authors: V
authors: Tropepe
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005136:Eye Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D055495:Neurogenesis / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000196:embryology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D017931:DNA Primers; C464523:Dmbx1a protein, zebrafish; D005136:Eye Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C108000:vsx2 protein, zebrafish; D019938:Cyclin D1; D001973:Bromodeoxyuridine
keywords: Cell cycle; Development; Differentiation; Fgf; Progenitor cell; Proliferation; Retina; Zebrafish; ccnd1; dmbx1; vsx2