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Nelms BL, Labosky PA. Transcriptional Control of Neural Crest Development. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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Transcriptional Control of Neural Crest Development.

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Chapter 11RAR /RXR Genes

Retinoic acid (RA) and retinoid signaling, particularly in the cranial NC, play a critical role in patterning NC derivatives. These signaling events are largely mediated by the retinoic acid receptors (RARs) and the retinoid receptors (RXRs), transcription factors that often bind their targets as heterodimers and recruit transcriptional repressor complexes. There are three RAR genes and three R XR genes conserved between humans, mice, chickens, fish, and frogs (RARα /β /γ, and RXRα /β /γ ). RA binding to RAR receptors induces a conformational change in the receptor, followed by the replacement of corepressor with coactivator complexes (Cvekl and Wang, 2009). In vitro, RARs bind to response elements as heterodimers with RXRs.

11.1. RARa, RARb, AND RARg

In the mouse embryo, RARa is associated with NCC emigration and migration. RARa and RARb are expressed at specific levels of the hindbrain and in the spinal cord (Ruberte et al., 1991). RA signaling acts at an early stage in primary neural development during fate determination of different regions of the neuroectoderm, and RARa expression in the posterior neuroectoderm is consistent with a role in primary neurogenesis (Sharpe and Goldstone, 2000). Null mutations of all six mouse RAR /RXR genes have been generated. RARα, β and γ single-null mutants have defects in only a small subset of the tissues normally expressing these receptors, but RAR double-null mutants have defects in most tissues, including those originating from the NC-derived mesenchyme, indicating functional redundancy or dosage dependence (Mark et al., 1998). RARa-null; RARβ-null compound mutants display defects in structures partially derived from the mesenchymal and neurogenic NC such as the thymus and post-otic cranial nerves, respectively. Lack of RARa and RARb has no direct effect on the number and migration path of NCCs, but Mafb and Krox20 expression domains are expanded, Hoxb1 and Hoxb3 are ectopically upregulated, and Hoxd4 expression is lost (Dupe et al., 1999). Treatment of cultured mouse embryos with synthetic RARb, acting through the endodermal cells lining the pharyngeal arches but not the NCCs or ectoderm, causes hypoplasia and fusion of pharyngeal arches 1 and 2, typical of RA-related defects. This synthetic RARb agonist also antagonizes RARa and RARg (Matt et al., 2003). RARa is the only receptor mediating retinoid signaling in the neurectoderm during ocular development, but all three RARs mediate the action of RA during eye morphogenesis, specifically in NC-derived periocular mesenchyme (Cvekl and Wang, 2009; Matt et al., 2008). Inactivation of RARa/b/g receptors in the periocular mesenchyme abrogates anterior eye segment formation (Cvekl and Wang, 2009). One identified target of RARa in neuroblastoma and NC-derived cells is the developmentally regulated, retinoid-responsive thymosin b10 gene (Hall, 1992).

11.2. RXRa, RXRb, AND RXRg

The RARs often function in heterodimers with RXRs. Mutant embryos lacking different combinations of both RARs and RXRs indicate that RXRa:RARg heterodimers are instrumental in patterning craniofacial skeletal elements, whereas RXRa:RARa heterodimers may be preferentially involved in generation of NC-derived arterial smooth muscle cells (Mark et al., 1998). Both RXRa:RARb and RXRa:RARg heterodimers function in development of the ocular mesenchyme (Mark et al., 1998).

In the trunk region, RXR transcripts are expressed by cells in the premigratory NC and in NCCs migrating through the sclerotome, indicating that NCCs express RXR transcripts before differentiation to PNS derivatives, suggesting a role for RA, mediated by RXR, in the developing PNS. Chicken RXRa is expressed at high levels during development of the NC-derived PNS, including DRG, cranial ganglia, enteric ganglia, and peripheral nerve tracts (Rowe et al., 1991). RXRa-null mouse embryos die in utero between E13.5 and E16.5 due to ventricular hypoplasia, but the NC-contributed OFT and associated vessels are normal (Sucov et al., 1994). During early chicken embryogenesis, RXRa transcripts are present in the CNS and at reduced levels in the NC and limb buds. RA upregulates RXRa transcripts at some stages but not does not expand the expression domain (Hoover and Glover, 1998). RXRg marks migrating cranial NCCs in the chicken embryo and is gradually restricted to specific differentiating neurogenic NC derivatives such as the TG and DRGs (Rowe and Brickell, 1995, 1031). Unlike the chicken, where RXRg is expressed from the onset of NC migration, in rat embryos, only RXRg expression later in the DRG and TG, which is not detected until E14.5, is conserved (Georgiades et al., 1998).

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53134

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