Seminars in Cell & Developmental Biology 16 (2005) 683–693 Review Specification of neural crest cell formation and migration in mouse embryos Paul A. Trainor ∗ Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110, USA Available online 25 July 2005 Abstract Of all the model organisms used to study human development, rodents such as mice most accurately reflect human craniofacial development. Collective advances in mouse embryology and mouse genetics continue to shape our understanding of neural crest cell development and by extrapolation the etiology of human congenital head and facial birth defects. The aim of this review is to highlight the considerable progress being made in our understanding of cranial neural crest cell patterning in mouse embryos. © 2005 Elsevier Ltd. All rights reserved. Keywords: Mouse; Neural crest; Craniofacial; Induction; Migration Contents 1. Introduction ......................................................................................................... 683 2. Mouse neural crest cells: formation, migration, differentiation ............................................................ 684 3. Specification of mouse neural crest cell formation ....................................................................... 685 4. Specification of mouse neural crest cell migration ....................................................................... 687 5. Specification of multipotency versus restricted potency of mouse neural crest cells .......................................... 690 6. Conclusions ......................................................................................................... 690 Acknowledgements .................................................................................................. 690 References .......................................................................................................... 691 1. Introduction form very early during craniofacial development and they generate the majority of the cartilage, bone, connective and The craniofacial complex is anatomically the most sophis- peripheral nerve tissue in the head (Fig. 1). Not only are ticated part of the body and to function properly it requires neural crest cells crucial to head development but they are the orchestrated integration of the viscerocranium and also synonymous with vertebrate craniofacial evolution. neurocranium, the central and peripheral nervous systems, Craniofacial abnormalities are largely attributed to defects facial muscles, connective tissue, vasculature and dermis. in the formation, migration and differentiation of neural crest Not surprisingly this integration often goes awry such that cells and the origins of particular congenital syndromes can craniofacial abnormalities are the most common congenital be traced back specifically to problems in one or more of these malformation constituting at least a third of all birth defects. phases of neural crest cell development. For example, First Neural crest cells, are a migratory stem cell population that Arch syndrome broadly describes craniofacial abnormalities characterized by malformation of the eyes, ears, lower jaw ∗ Tel.: +1 816 926 4414; fax: +1 816 926 2051. and palate. Treacher Collins syndrome and Pierre Robin syn- E-mail address: [email protected]. drome are two of the more extreme examples falling into this 1084-9521/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2005.06.007 684 P.A. Trainor / Seminars in Cell & Developmental Biology 16 (2005) 683–693 Fig. 1. Migration and differentiation of neural crest cells. Sox10 in situ hybridization (purple stain) labels the distinct segregated streams of neural crest cells as they leave the neural tube of mouse embryos at 8.5 dpc (A) and as they condense to contribute to the cranial ganglia at 9.5 dpc (B). Neurofilament immunohistochemistry highlights the differentiation of neural crest cells in the cranial ganglia into sensory neurons that project axons into the branchial arches at 10.5 dpc (C). Neural crest cells also give rise to the majority of the cartilage (blue) and bone (red) that constitute the viscerocranium and neurocranium (D, sagittal view; E, superior view). category. The clinical abnormalities associated with Treacher earliest known markers of neural crest cell formation and the Collins and Pierre Robin syndromes are thought to arise due onset of their expression has been used to study the spatial to defects in the migration of neural crest cells. In contrast, and temporal competence of the neural plate to initiate neural craniosynostoses, which are characterized by the premature crest induction in response to different signals. fusion of the bony plates in the skull are related to problems Murine neural crest cell formation and migration com- with neural crest cell differentiation [1–3]. Consequently it is mences at approximately the 4–5 somite stage in the region important to understand the distinct mechanisms, which reg- of the caudal midbrain and rostral hindbrain [7] and proceeds ulate the formation, migration and differentiation of neural simultaneously as a wave rostrally towards the forebrain and crest cells. caudally towards the tail (Fig. 1). In avian embryos neu- ral crest cell migration commences after neural tube closure however this is not the case in mammalian embryos such as 2. Mouse neural crest cells: formation, migration, mice where neural crest cell formation and migration com- differentiation mences well before fusion of the bilateral halves of the neural plate. Typically there is a narrow temporal window during Murine neural crest cells are generated transiently along which neural crest cells are induced to delaminate and emi- almost the entire vertebrate axis at the interface between the grate from the dorsal neural tube and although this period surface ectoderm and the neural plate of the embryo, in a varies between species, in mice it typically lasts mice 7–9 h at region that is referred to as the neural plate border. During this each axial level [8]. The neural crest can be subdivided rostro- induction process, neuroepithelial cells undergo an epithelial caudally into at least four distinct major axial populations; to mesenchymal transformation at which point they delam- cranial, cardiac, vagal and trunk, each of which migrates inate and begin to emigrate from the neural tube, a process along unique pathways, contributing to specific cell and tis- that requires significant cytoarchitectural and cell adhesive sue types that are characteristic of their axial level of origin. changes. The induction of the neural crest cells is typically The cranial neural crest, which is the focus of this assayed by the expression of members of the Snail (Snail review can be divided into forebrain, midbrain and hindbrain and Slug) zinc-finger transcription factors gene family [4,5], domains of migrating neural crest cells. Cranial neural crest which play key roles in the epithelial to mesenchymal trans- cells do not appear to migrate randomly, rather they follow formation process by repressing the cell adhesion molecule precise, species and region specific pathways moving subec- E-cadherin [6]. Snail/Slug transcription factors are among the todermally over the surface of the cranial mesoderm [8–10]. P.A. Trainor / Seminars in Cell & Developmental Biology 16 (2005) 683–693 685 Cranial neural crest cells typically migrate in discrete seg- These results are eagerly anticipated as they will substantially regated streams, the pattern of which is highly conserved aid comparative analysis of neural crest cell patterning in in vertebrate species as disparate as amphibians, teleosts, diverse organisms and further our understanding of neural avians, marsupials and mammals (reviewed in [11]). Briefly, crest cell and craniofacial evolution. forebrain and rostral midbrain neural crest cells colonise the Collectively these analyses performed in mice together frontonasal and periocular regions. Caudal midbrain derived with those from avians, fish and frogs demonstrate that neural crest cells populate the maxillary component of the cardiac, vagal and trunk neural crest cells produce neurons, first branchial arch [9,10]. The hindbrain is divided into glial cells, secretory cells and pigment cells—contributing seven distinct segments known as rhombomeres [12] and to the peripheral nervous system, enteric nervous system, neural crest cells emigrate from each of the rhombomeres, endocrine system and skin. Cranial neural crest cells however but predominantly from rhombomeres 2, 4 and 6 in discrete exhibit an even more surprising diversity of derivatives, segregated streams that populate the first, second and third giving rise to pigment cells, nerve ganglia, smooth muscle, branchial arches respectively [9,10]. and connective tissue, as well as most of the bone and Exquisite fate mapping analyses particularly in avians cartilage of the head (Fig. 1). using the quail-chick chimera system, have revealed that neu- ral crest cells derived from each axial region of the cranial neural plate and in particular from each individual rhom- 3. Specification of mouse neural crest cell formation bomere generate specific and unique components of the cran- iofacial complex including the viscero- and neurocraniums Neural crest cell formation requires contact mediated sig- as well as the peripheral nervous system [13–16]. Despite the nals between the neural plate and paraxial tissues such as generation of lineage fate maps in mice [9,10],