Retinoic acid and hindbrain patterning

Abstract

Retinoid signaling plays an important role in the developmental patterning of the hindbrain. Studies of the teratogenic effects of retinoids showed early on that the hindbrain suffered patterning defects in cases of retinoid excess or deficiency. Closer examination of these effects in animal models suggested that retinoids might play a physiological role in specifying the antero-posterior axis of the hindbrain. This idea was supported by the localization of retinoid synthetic and degradative enzymes, binding proteins, and receptors to the hindbrain and neighboring regions of the neuroepithelium and the mesoderm. In parallel, it became clear that the molecular patterning of the hindbrain, in terms of the regionalized expression of Hox genes and other developmental regulatory genes, is profoundly influenced by retinoid signaling.

Genetic disruption of CYP26B1 severely affects development of neural crest derived head structures, but does not compromise hindbrain patterning

“…Cyp26a1 null mutant mice exhibit a mild defect in hindbrain patterning, and Cyp26a1/ Cyp26c1 double knockout animals have an enlarged posterior hindbrain at the expense of anterior structures (AbuAbed et al, 2001;Uehara et al, 2007). These genetic models support observations in zebrafish, chick and frog that RA may act as a posteriorizing signal in the hindbrain, and correct RA-mediated signaling is required for NCC development (Glover et al, 2006).…”

“…The finely tuned distribution of RA is critical for normal hindbrain development; numerous studies in the chick, rodent, frog and zebrafish have shown that perturbations in RA localization can disrupt hindbrain formation (Glover et al, 2006). This distribution of endogenous RA is established through the dynamic expression of Raldh2 and the Cyp26 genes.…”

Retinoic acid signaling in development: Tissue‐specific functions and evolutionary origins

“…Clinical and basic research carried out in the last 50 years has established that the vitamin A-derived morphogen retinoic acid (RA) is an important modulator of cell survival, cellular proliferation, differentiation, regionalization, and organogenesis in the developing embryo (reviewed in Blomhoff and Blomhoff, 2006;Glover et al, 2006;Mark et al, 2006). Moreover, effects of RA on epithelial and tumor cells have also led to the use of vitamin A derivatives (generally referred to as retinoids) as anti-tumor agents and as therapeutic products to cure skin illnesses (Kligman, 1997).…”

“…The roles of RA during development have been extensively investigated in vertebrates (chiefly in rodents, chicken and quail, frogs and fish) (reviewed in Glover et al, 2006;Maden, 2002;Mark et al, 2006). Although vitamin A deficiency models and pharmacological approaches, such as treatment with vitamin A or RA, were initially used to study RA signaling, the development of genetic tools, such as targeted gene knockouts, has allowed an even more detailed assessment of the roles of RA during vertebrate embryogenesis.…”

A novel method for retinoic acid administration reveals differential and dose‐dependent downregulation of Fgf3 in the developing inner ear and anterior CNS

“…Exposure at presomitic stages (7.75 dpc and earlier) leads to extensive changes in hindbrain patterning, where there is a shortening of the hindbrain and the hindbrain also adopts a more posterior identity (Wood et al, 1994;Glover et al, 2006). In order to address whether the changes noted above in Fgf3 otic expression are secondary to a hindbrain patterning/identity defect, we also analysed the effects on Fgf3 expression of RA exposure to early somite-stage embryos (8.5 dpc, approximately 8-12 somites), a stage where the identity of the posterior hindbrain is unchanged by administration of RA (Wood et al, 1994;Glover et al, 2006).…”