Homeobox transcription factors regulate retinoic acid signaling during vertebrate nervous system development.

摘要

During development, signaling pathways are tightly regulated to achieve correct patterning of the embryo along the anterior-posterior, dorsal-ventral, and left-right axes. In the absence of correct patterning signals, the misspecification of neuronal identity can have severe phenotypic consequences. The congenital syndrome holoprosencephaly is thought to arise from such mispatterning, where forebrain progenitors are improperly specified, and results in a broad spectrum of neural and craniofacial defects. In the most severe cases, affected individuals have a complete absence of midline or ventral cell types, concomitant with cyclopia.;This work began with a gene linked to holoprosencephaly, TGIF . Previous work suggests that TGIF may regulate the Nodal or RA pathways to regulate forebrain development. I examined if Tgif regulates these two pathways during zebrafish neural patterning. While there is no detectable genetic interaction between Tgif and the Nodal pathway, Tgif is a novel regulator of retinoic acid metabolism gene expression.;To identify potential Tgif effectors, I performed microarray analysis. hmx4 (H6 homeobox 4) was identified as a Tgif-regulated gene. Other HMX genes are important for nervous system development, and hmx4 was therefore chosen for further study. We find that hmx4 is a novel regulator of RA metabolism gene expression, although in a manner distinct from Tgif Interestingly, Hmx4-depleted embryos also display cyclopia. In addition to being a regulator of RA signaling, we find that Hmx4 has a dual role as a regulator of Shh signaling. This positions hmx4 as a potential mechanism for coordinating the activity of these two essential developmental signaling pathways, and yields novel insights into the regulation of vertebrate neural patterning.;Retinoic acid (RA) is a morphogen known for its important role in anterior-posterior neural patterning, while Sonic hedgehog (Shh) and Nodal signaling are two of the best characterized dorsal-ventral signals. Aberrant levels of signaling activity of any of these three pathways cause phenotypes within the holoprosencephaly spectrum, in both human patients and animal models. While the genetic intricacies of these three pathways have been extensively studied, how they are regulated and coordinated within the embryo is poorly understood.