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SummaryDuring vertebrate craniofacial development, neural crest cells (NCCs) contribute much of the cartilage, bone and connective tissue that make up the developing head. Although the initial patterns of NCC segmentation and migration are conserved between species, the variety of vertebrate facial morphologies that exist indicates that a complex interplay occurs between intrinsic genetic NCC programs and extrinsic environmental signals during morphogenesis. Here, we review recent work that has begun to shed light on the molecular mechanisms that govern the spatiotemporal patterning of NCC-derived skeletal structures -advances that are central to understanding craniofacial development and its evolution.

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Neural progenitor cells often produce distinct types of neurons in a specific order, but the determinants that control the sequential generation of distinct neuronal subclasses in the vertebrate CNS remain poorly defined. We examined the sequential generation of visceral motor neurons and serotonergic neurons from a common pool of neural progenitors located in the ventral hindbrain. We found that the temporal specification of these neurons varies along the anterior-posterior axis of the hindbrain, and that the timing of their generation critically depends on the integrated activities of Nkx-and Hox-class homeodomain proteins. A primary function of these proteins is to coordinate the spatial and temporal activation of the homeodomain protein Phox2b, which in turn acts as a binary switch in the selection of motor neuron or serotonergic neuronal fate. These findings assign new roles for Nkx, Hox, and Phox2 proteins in the control of temporal neuronal fate determination, and link spatial and temporal patterning of CNS neuronal fates. Neuronal cell diversity is established by mechanisms that operate in space and over time during central nervous system (CNS) development. Insight has been obtained regarding the initial steps of spatial patterning of neurons along the dorsal-ventral (DV) and anterior-posterior (AP) axes of the neural tube Jessell 2000). Local inductive signals determine the spatial pattern of expression of transcription factors along both these axes, so that neural progenitors at different positions acquire distinct molecular identities. In the ventral neural tube, neuronal fate along the DV axis depends on the Shh-mediated patterning of Nkx-, Dbx-, Pax-, and Irx-class homeodomain (HD) proteins . Along the AP axis, the overlapping, or nested, expression pattern of Hox HD proteins provides positional values that influence the fate of neurons . Despite significant advances, however, DV and AP patterning have generally been analyzed independently, leaving open the issue as to what degree these orthogonal patterning mechanisms are integrated (Davenne et al. 1999;Gaufo et al. 2000). Compared to spatial patterning, little is known about the mechanisms that underlie how neural progenitors produce distinct types of neurons in a specific temporal order. Studies of the retina (Livesey and Cepko 2001) and developing neo-cortex (Monuki and Walsh 2001) suggest that the sequential production of different neuronal subtypes reflects temporal changes in neural progenitors, either in response to extrinsic cues or mechanisms intrinsic to neural progenitor cells. Recent data indicate that modulation of Notch signaling by the bHLH protein Mash1 and the HD proteins Dlx1/2 may control the sequential specification of progenitors in subcortical areas of the telencephalon (Yun et al. 2002). Apart from this, few molecular determinants that influence these temporal processes in the vertebrate CNS have been identified to date. ResultsTo address how spatial and temporal aspects of cell patterning are integrated during development, w...

Rhombomeres (r) contribute to brainstem auditory nuclei during development. Hox genes are determinants of rhombomere-derived fate and neuronal connectivity. Little is known about the contribution of individual rhombomeres and their associated Hox codes to auditory sensorimotor circuitry. Here, we show that r4 contributes to functionally linked sensory and motor components, including the ventral nucleus of lateral lemniscus, posterior ventral cochlear nuclei (VCN), and motor olivocochlear neurons. Assembly of the r4-derived auditory components is involved in sound perception and depends on regulatory interactions between Hoxb1 and Hoxb2. Indeed, in Hoxb1 and Hoxb2 mutant mice the transmission of low-level auditory stimuli is lost, resulting in hearing impairments. On the other hand, Hoxa2 regulates the Rig1 axon guidance receptor and controls contralateral projections from the anterior VCN to the medial nucleus of the trapezoid body, a circuit involved in sound localization. Thus, individual rhombomeres and their associated Hox codes control the assembly of distinct functionally segregated sub-circuits in the developing auditory brainstem.

In the mouse trigeminal pathway, sensory inputs from distinct facial structures, such as whiskers or lower jaw and lip, are topographically mapped onto the somatosensory cortex through relay stations in the thalamus and hindbrain. In the developing hindbrain, the mechanisms generating such maps remain elusive. We found that in the principal sensory nucleus, the whisker-related map is contributed by rhombomere 3-derived neurons, whereas the rhombomere 2-derived progeny supply the lower jaw and lip representation. Moreover, early Hoxa2 expression in neuroepithelium prevents the trigeminal nerve from ectopically projecting to the cerebellum, whereas late expression in the principal sensory nucleus promotes selective arborization of whisker-related afferents and topographic connectivity to the thalamus. Hoxa2 inactivation further results in the absence of whisker-related maps in the postnatal brain. Thus, Hoxa2- and rhombomere 3-dependent cues determine the whisker area map and are required for the assembly of the whisker-to-barrel somatosensory circuit.

The homeobox, a 60-amino acid-encoding DNA sequence, originally discovered in the genome of the fruit fly Drosophila, was subsequently identified throughout the three kingdoms of multicellular organisms. Homeobox-containing genes encode DNA-binding proteins that regulate gene expression and control various aspects of morphogenesis and cell differentiation. In particular, the Hox family of clustered homeobox genes plays a fundamental role in the morphogenesis of the vertebrate embryo, providing cells with regional information along the main body axis. The nonclustered or divergent homeobox genes include a large number of genes scattered throughout the genome that, nevertheless, can be organized in distinct families based on their homologies and functional similarities. This review will provide the reader with a brief overview on some recent studies aimed at understanding the functional role of homeobox genes in normal mammalian development as well as their involvement in congenital malformations and oncogenesis.

Little is known about how the generation of specific neuronal types at stereotypic positions within the hindbrain is linked to Hox gene-mediated patterning. Here, we show that during neurogenesis, Hox paralog group 2 genes control both anteroposterior (A-P) and dorsoventral (D-V) patterning. Hoxa2 and Hoxb2 differentially regulate, in a rhombomere-specific manner, the expression of several genes in broad D-V-restricted domains or narrower longitudinal columns of neuronal progenitors, immature neurons, and differentiating neuronal subtypes. Moreover, Hoxa2 and Hoxb2 can functionally synergize in controlling the development of ventral neuronal subtypes in rhombomere 3 (r3). Thus, in addition to their roles in A-P patterning, Hoxa2 and Hoxb2 have distinct and restricted functions along the D-V axis during neurogenesis, providing insights into how neuronal fates are assigned at stereotypic positions within the hindbrain.