Molecular Regulation of Facial Development

As indicated, much of the face is derived from neural crest cells that migrate into the pharyngeal arches from the edges of the cranial neural folds. In the hind-brain, crest cells originate from segmented regions known as rhombomeres. There are eight of these segments in the hindbrain (R1 to R8), and crest cells

Figure 15.12 Patterns of neural crest cell migration into the pharyngeal arches and of HOX gene expression in rhombomeres of the hindbrain. HOX genes are expressed in overlapping patterns with those at the 3' end having the most rostral boundaries. This pattern specifies derivatives of each of the rhombomeres, including crest cells and their pathways of migration. The first arch is also populated by crest cells from the midbrain. These cells express OTX2, a transcription factor containing a homeodomain.

from specific segments populate specific arches (Fig. 15.12). Crest cells from R1 and R2 migrate to the first arch, cells from R4 go to the second arch, those from R6 and 7 to the third arch, and those from R8 to the fourth and sixth arches. In addition, the first arch receives crest cells originating in the mid-brain. Few if any crest cells form from R3 and R5. Most of the cells from these rhombomeres undergo cell death by apoptosis, while a few migrate with crest cells originating from adjacent segments.

Patterning of pharyngeal arches (with exception of the first arch) is regulated by HOX genes carried by migrating neural crest (Fig. 15.12). Expression of HOX genes in the hindbrain occurs in specific overlapping patterns, such that the most 3' genes in a cluster have the most rostral boundaries (Fig. 15.12). Since 3' genes are the first to be expressed, a temporal relationship for HOX gene expression is also established in a rostrocaudal sequence. In addition, paralogous genes, for example HOXA3, HOXB3, and HOXD3 (see Chapter 5 and Fig. 5.22), share identical expression domains. These expression patterns determine the organization of cranial ganglia and nerves and pathways of neural crest migration. Initially, crest cells express the HOX genes from their segment of origin, but maintenance of this specific expression is dependent upon interaction of these cells with mesoderm in the pharyngeal arches. For example, crest cells from the second arch express HOXA2, and if these cells interact with second arch mesoderm, then this expression continues (Fig. 15.13). However, if second arch crest is placed into the first arch, this expression is down-regulated. Thus, although an overlapping HOX code is essential to specifying the identity of the arches and their derivatives, crest cells alone do not establish or maintain the expression pattern. How the code is translated to control

Figure 15.13 Schematic drawing showing the relationship between the first two pharyngeal arches (PA1 and PA2), segmentation of a region of the hindbrain at rhom-bomeres 2-5 (r2-r5), and pathways of neural crest cell migration (colors). A HOXcode is established in the hindbrain that specifies the arches and pathways of neural crest cell migration (with exception of PA1). Maintenance of the code in the arches is dependent upon an interaction between crest cells and arch-specific mesoderm. Patterning of the arches into their derivatives requires epithelial-mesenchymal interactions and includes molecular signals from the surface ectoderm, i.e., fibroblast growth factors (FGFs) acting upon underlying mesenchyme cells. OV, otic vesicle.

differentiation of the arches is not known, but a host of upstream and downstream genes must be involved. Sonic hedgehog may be one of the upstream regulators, since it is expressed in the arches and has been shown to regulate HOX gene expression. Retinoids (retinoic acid) can also regulate HOX gene expression in a concentration-dependent manner with genes at the 3' end being more responsive than those in more 5' regions. Regulation occurs through retinoic acid response elements (RAREs), which are binding sites for retinoic acid in the promoter regions of the HOX genes. Deficiencies and excesses of retinoids disrupt migration and the axial identity of hindbrain crest cells, resulting in severe craniofacial defects.

In addition to the HOX genes, OTX2 may participate in morphogenesis of the first arch. This gene, a transcription factor important for brain development, contains a homeodomain and is expressed in forebrain and midbrain regions (see Chapter 19). Neural crest cells that migrate from the midbrain to the first arch carry OTX2 with them into this region. Presumably, OTX2 and possibly HOX genes in the first arch interact to pattern this structure.

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