Retinoic acid receptors exhibit cell‐autonomous functions in cranial neural crest cells

Abstract

Previous work has emphasized the crucial role of retinoic acid (RA) in the ontogenesis of the vast majority of mesenchymal structures derived from the neural crest cells (NCC), which migrate through, or populate, the frontonasal process and branchial arches. Using somatic mutagenesis in the mouse, we have selectively ablated two or three retinoic acid receptors (i.e., RARa/RARb, RARa/RARc and RARa/RARb/ RARc) in NCC. By rigorously analyzing these mutant mice, we found that survival and migration of NCC is normal until gestational day 10.5, suggesting that RAR-dependent signaling is not intrinsically required for the early steps of NCC development. However, ablation of Rara and Rarg genes in NCC yields an agenesis of the median portion of the face, demonstrating that RARa and RARc act cell-autonomously in postmigratory NCC to control the development of structures derived from the frontonasal process. In contrast, ablation of the three Rar genes in NCC leads to less severe defects of the branchial arches derived structures compared with Rar compound null mutants. Therefore, RARs exert a function in the NCC as well as in a separated cell population. This work demonstrates that RARs use distinct mechanisms to pattern cranial NCC. INTRODUCTIONThe morphogenesis of the craniofacial region results from complex developmental processes involving the migration of neural crest cells (NCC) and their subsequent differentiation through interactions with endoderm and ectoderm (Veitch et al., 1999;Trainor and Krumlauf, 2001). Cranial NCC arise from fore-, mid-, and hindbrain in distinct migratory streams. Fore-and midbrain NCC give rise to the frontonasal skeleton, whereas pre-otic hindbrain populations colonize the first two branchial arches (BAs), where they differentiate to form skeletal elements of the jaw, middle ear and tongue. Cardiac NCC participate in the development of aortic arch arteries, as well as thymus, thyroid, and parathyroid glands (Le Douarin et al., 1993;Santagati and Rijli, 2003). Because patterning and morphogenesis of these craniofacial structures require a finely orchestrated series of tissue interactions (Graham and Smith, 2001;Trainor and Krumlauf, 2001), perturbation of different processes may yield similar developmental abnormalities. For instance, inactivation of genes expressed in either NCC, endoderm, or ectoderm, results in similar cardiovascular defects, as remodeling of BA arteries into the definitive arterial vessels and heart outflow tract requires coordinated communication between NCC, endoderm and ectoderm (Depew ABBREVIATIONS BA branchial arch E embryonic day NCC neural crest cells RA retinoic acid ALDH1A retinaldehyde dehydrogenase RAR retinoic acid receptor RXR rexinoid receptor VAD vitamin A-deficient

Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development

“…Whereas RAR and RAR act cell-autonomously in NCCs, RAR is dispensable (Dupe and Pellerin, 2009). A local source of RA in the chick rostral head coordinates FNP morphogenesis through Fgf8 and Shh induction in the forebrain and facial ectoderm (Schneider et al, 2001) (Fig.…”

“…The double inactivations of RAR and RAR, or RAR and RAR, induce PA hypoplasia and NCC-derived cartilage malformations (Dupe et al, 1999;Lohnes et al, 1994;Mendelsohn et al, 1994;Wendling et al, 2000). However, the endoderm could be the primary target of RA action in mediating morphogenesis of PA2 and more posterior arches , as RARs are mostly dispensable in cranial NCCs (Dupe and Pellerin, 2009). Not only RA deficiency, but also exogenous RA excess during pregnancy or the inactivation of the cytochrome P450 (Cyp) RA-degrading enzymes induce teratogenesis in the craniofacial region (Abu-Abed et al, 2001;Maclean et al, 2009;Mulder et al, 2000;Reijntjes et al, 2007;Uehara et al, 2007).…”

Vitamin A in Reproduction and Development

“…Frontonasal agenesis has been reported in compound RAR null mutant mice [97] and RBP null mutant mice on a vitamin A-deficiency diet [110]. Dupe and Pellerin recently showed that selective ablation of RARα and RARγ subtypes using the Wnt1-Cre promoter leads to agenesis of the frontonasal skeletal elements, but does not appear to adversely affect the early survival and migration of neural crest cells [227]. Deletion of all three RAR subtypes using the selective promoter produces a similar phenotype, indicating that RARα and RARγ act cell-autonomously in neural crest cells to direct morphogenesis of these skeletal elements.…”

Fate of retinoic acid–activated embryonic cell lineages

“…These include (i) the ''first heart field'' or cardiac crescent formed from mesoderm emerging from the primitive streak (Garcia-Martinez and Schoenwolf, 1993;Tam et al, 1997); (ii) the ''second heart field'' originating from pharyngeal mesoderm (Buckingham et al, 2005); (iii) the (pro)epicardium, a population originating and giving rise to coronary vasculature, myocardial fibroblasts and to a distinct cardiomyocytic lineage (Cai et al, 2008;Zhou et al, 2008), and (iv) the ''cardiac'' neural crest, a subset of post-otic neural crest cells migrating through the third to sixth branchial arches and participating to the development of the aortic arches and aorticopulmonary septum (reviewed by Rochais et al, 2009). All these lineages have been reported to be influenced by embryonic RA (Hochgreb et al, 2003;Ryckebusch et al, 2008;Sirbu et al, 2008;Dupe and Pellerin, 2009), although recent studies implicate the second heart field (Ryckebusch et al, 2008;Sirbu et al, 2008) and the epicardium (Merki et al, 2005;Lin et al, 2010) as the main sites of RA signaling.…”