Paul A. Trainor

Relations and interactions between cranial mesoderm and neural crest populations

The embryonic head is populated by two robust mesenchymal populations, paraxial mesoderm and neural crest cells. Although the developmental histories of each are distinct and separate, they quickly establish intimate relations that are variably important for the histogenesis and morphogenesis of musculoskeletal components of the calvaria, midface and branchial regions. This review will focus first on the genesis and organization within nascent mesodermal and crest populations, emphasizing interactions that probably initiate or augment the establishment of lineages within each. The principal goal is an analysis of the interactions between crest and mesoderm populations, from their first contacts through their concerted movements into peripheral domains, particularly the branchial arches, and continuing to stages at which both the differentiation and the integrated three‐dimensional assembly of vascular, connective and muscular tissues is evident. Current views on unresolved or contentious issues, including the relevance of head somitomeres, the processes by which crest cells change locations and constancy of cell–cell relations at the crest–mesoderm interface, are addressed.

Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function.

Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1–mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1–driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.

Patterning the cranial neural crest: Hinbrain segmentation and hox gene plasticity

Understanding the patterning mechanisms that control head development — particularly the neural crest and its contribution to bones, nerves and connective tissue — is an important problem, as craniofacial anomalies account for one-third of all human congenital defects. Classical models for craniofacial patterning argue that the morphogenic program and Hox gene identity of the neural crest is pre-patterned, carrying positional information acquired in the hindbrain to the peripheral nervous system and the branchial arches. Recently, however, plasticity of Hox gene expression has been observed in the hindbrain and cranial neural crest of chick, mouse and zebrafish embryos. Hence, craniofacial development is not dependent on neural crest pre-patterning, but is regulated by a more complex integration of cell and tissue interactions.

Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities

Neural crest cells are a migratory cell population that give rise to the majority of the cartilage, bone, connective tissue, and sensory ganglia in the head. Abnormalities in the formation, proliferation, migration, and differentiation phases of the neural crest cell life cycle can lead to craniofacial malformations, which constitute one-third of all congenital birth defects. Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. Although TCS results from autosomal dominant mutations of the gene TCOF1, the mechanistic origins of the abnormalities observed in this condition are unknown, and the function of Treacle, the protein encoded by TCOF1, remains poorly understood. To investigate the developmental basis of TCS we generated a mouse model through germ-line mutation of Tcof1. Haploinsufficiency of Tcof1 leads to a deficiency in migrating neural crest cells, which results in severe craniofacial malformations. We demonstrate that Tcof1/Treacle is required cell-autonomously for the formation and proliferation of neural crest cells. Tcof1/Treacle regulates proliferation by controlling the production of mature ribosomes. Therefore, Tcof1/Treacle is a unique spatiotemporal regulator of ribosome biogenesis, a deficiency that disrupts neural crest cell formation and proliferation, causing the hypoplasia characteristic of TCS craniofacial anomalies.

Hox genes, neural crest cells and branchial arch patterning

Proper craniofacial development requires the orchestrated integration of multiple specialized tissue interactions. Recent analyses suggest that craniofacial development is not dependent upon neural crest pre-programming as previously thought but is regulated by a more complex integration of cell and tissue interactions. In the absence of neural crest cells it is still possible to obtain normal arch patterning indicating that neural crest is not responsible for patterning all of arch development. The mesoderm, endoderm and surface ectoderm tissues play a role in the patterning of the branchial arches, and there is now strong evidence that Hoxa2 acts as a selector gene for the pathways that govern second arch structures.

Defects in pathfinding by cranial neural crest cells in mice lacking the neuregulin receptor ErbB4

Mouse embryos with a loss-of-function mutation in the gene encoding the receptor tyrosine kinase ErbB4 exhibit misprojections of cranial sensory ganglion afferent axons. Here we analyse ErbB4-deficient mice, and find that morphological differences between wild-type and mutant cranial ganglia correlate with aberrant migration of a subpopulation of hindbrain-derived cranial neural crest cells within the paraxial mesenchyme environment. In transplantation experiments using new grafting techniques in cultured mouse embryos, we determine that this phenotype is non-cell-autonomous: wild-type and mutant neural crest cells both migrate in a pattern consistent with the host environment, deviating from their normal pathway only when transplanted into mutant embryos. ErbB4 signalling events within the hindbrain therefore provide patterning information to cranial paraxial mesenchyme that is essential for the proper migration of neural crest cells.

Treacher Collins syndrome : etiology, pathogenesis and prevention

Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development that arises as the result of mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein known as Treacle. Individuals diagnosed with TCS frequently undergo multiple reconstructive surgeries, which are rarely fully corrective. Identifying potential avenues for rescue and/or repair of TCS depends on a profound appreciation of the etiology and pathogenesis of the syndrome. Recent research using animal models has not only determined the cellular basis of TCS but also, more importantly, unveiled a successful avenue for therapeutic intervention and prevention of the craniofacial anomalies observed in TCS.

Neural crest stem cells: discovery, properties and potential for therapy

Neural crest (NC) cells are a migratory cell population synonymous with vertebrate evolution. They generate a wide variety of cell and tissue types during embryonic and adult development including cartilage and bone, connective tissue, pigment and endocrine cells as well as neurons and glia amongst many others. Such incredible lineage potential combined with a limited capacity for self-renewal, which persists even into adult life, demonstrates that NC cells bear the key hallmarks of stem and progenitor cells. In this review, we describe the identification, characterization and isolation of NC stem and progenitor cells from different tissues in both embryo and adult organisms. We discuss their specific properties and their potential application in cell-based tissue and disease-specific repair.

Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models.

Retinoic acid (RA) is the active metabolite of vitamin A (retinol) that controls growth and development. The first step of RA synthesis is controlled by enzymes of the alcohol dehydrogenase (ADH) and retinol dehydrogenase (RDH) families that catalyze oxidation of retinol to retinaldehyde. The second step of RA synthesis is controlled by members of the aldehyde dehydrogenase (ALDH) family also known as retinaldehyde dehydrogenase (RALDH) that further oxidize retinaldehyde to produce RA. RA functions as a ligand for DNA-binding RA receptors that directly regulate transcription of specific target genes. Elucidation of the vitamin A metabolic pathway and investigation of the endogenous function of vitamin A metabolites has been greatly improved by development of mouse ADH, RDH, and RALDH loss-of-function models. ADH knockouts have demonstrated a postnatal role for this enzyme family in clearance of excess retinol to prevent vitamin A toxicity and in generation of RA for postnatal survival during vitamin A deficiency. A point mutation in Rdh10 generated by ethylnitrosourea has demonstrated that RDH10 generates much of the retinaldehyde needed for RA synthesis during embryonic development. Raldh1, Raldh2, and Raldh3 knockouts have demonstrated that RALDH1, RALDH2, and RALDH3 generate most of the RA needed during embryogenesis. These mouse models serve as instrumental tools for providing new insight into retinoid function. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.

Comparative analysis of neural crest cell death, migration, and function during vertebrate embryogenesis

Cranial neural crest cells are a multipotent, migratory population that generates most of the cartilage, bone, connective tissue and peripheral nervous system in the vertebrate head. Proper neural crest cell patterning is essential for normal craniofacial morphogenesis and is highly conserved among vertebrates. Neural crest cell patterning is intimately connected to the early segmentation of the neural tube, such that neural crest cells migrate in discrete segregated streams. Recent advances in live embryo imaging have begun to reveal the complex behaviour of neural crest cells which involve intricate cell‐cell and cell‐environment interactions. Despite the overall similarity in neural crest cell migration between distinct vertebrates species there are important mechanistic differences. Apoptosis for example, is important for neural crest cell patterning in chick embryos but not in mouse, frog or fish embryos. In this paper we highlight the potential evolutionary significance of such interspecies differences in jaw development and evolution. Developmental Dynamics 229:14–29, 2004.