Molecular Regulation of Brain Development

Anteroposterior (craniocaudal) patterning of the central nervous system begins early in development, during gastrulation and neural induction (see Chapters 4 and 5). Once the neural plate is established, signals for segregation of the brain into forebrain, midbrain, and hindbrain regions are derived from homeobox genes expressed in the notochord, prechordal plate, and neural plate. The hind-brain has eight segments, the rhombomeres, that have variable expression patterns of the Antennapedia class of homeobox genes, the HOX genes (see Chapter 5). These genes are expressed in overlapping patterns, with genes at the most 3' end of a cluster having more anterior boundaries and paralogous genes having identical expression domains (Fig. 19.31). Genes at the 3' end are also expressed earlier than those at the 5' end, so that a temporal relation

Figure 19.31 Patterns of HOX gene expression in the hindbrain and the pattern of neural crest cell migration into the pharyngeal arches. HOX genes are expressed in overlapping patterns ending at specific rhombomere boundaries. Genes at the 3' end of a cluster have the most anterior boundaries, and paralogous genes have identical expression domains. These genes confer positional value along the anterior-posterior axis of the hindbrain, determine the identity of the rhombomeres, and specify their derivatives.

to the expression pattern is established. These genes, then, confer positional value along the anteroposterior axis of the hindbrain, determine the identity of the rhombomeres, and specify their derivatives. How this regulation occurs is not clear, although the retinoids (retinoic acid) play a critical role in regulating HOX expression. For example, excess retinoic acid shifts HOX gene expression anteriorly and causes more cranial rhombomeres to differentiate into more caudal types. Retinoic acid deficiency results in a small hindbrain. There is also a differential response to retinoic acid by the HOX genes; those at the 3' end of the cluster are more sensitive than those at the 5' end.

Specification of the forebrain and midbrain areas is also regulated by genes containing a homeodomain. However, these genes are not of the Antennapedia class, whose most anterior boundary of expression stops at rhombomere 3. Thus, new genes have assumed the patterning role for these regions of the

Figure 19.32 Overlapping expression patterns of homeobox genes that specify the identities of the forebrain and midbrain regions.

brain, which evolutionarily constitute the "new head." At the neural plate stage, LIM1, expressed in the prechordal plate, and OTX2, expressed in the neural plate, are important for designating the forebrain and midbrain areas, with LIM1 supporting OTX2 expression. (These genes are also expressed at the earliest stages of gastrulation, and they assist in specifying the entire cranial region of the epiblast.) Once the neural folds and pharyngeal arches appear, additional homeobox genes, including OTX1, EMX1, and EMX2 are expressed in specific and in overlapping (nested) patterns (Fig. 19.32) that specify the identity of the forebrain and midbrain regions. Once these boundaries are established, two additional organizing centers appear: the anterior neural ridge (ANR) at the junction of the cranial border of the neural plate and nonneural ectoderm (Fig. 19.33) and the isthmus (Fig. 19.34) between the hindbrain and midbrain. In both locations, fibroblast growth factor-8 (FGF-8) is the key signaling molecule, inducing subsequent gene expression that regulates differentiation. In the ANR at the four-somite stage, FGF-8 induces expression of brainfactor 1 (BF1; Fig. 19.33). BF1 then regulates development of the telencephalon (cerebral hemispheres) and regional specification within the forebrain, including the basal telencephalon and the retina. In the isthmus at the junction between the midbrain and hindbrain territories, FGF-8 is expressed in a ring around the circumference of this location (Fig. 19.34). FGF-8 induces expression of engrailed 1 and 2 (EN1 and EN2 ), two homeobox-containing genes, expressed in gradients radiating anteriorly and posteriorly from the isthmus. EN1 regulates development throughout its expression domain, including the dorsal mid-brain (tectum) and anterior hindbrain (cerebellum), whereas EN2 is involved only in cerebellar development. FGF-8 also induces WNT1 expression in a

Figure 19.33 Diagram illustrating the organizing center known as the anterior neural ridge (ANR). This area lies in the most anterior region of the neural plate and secretes FGF-8, which induces expression of brain factor 1 (BF1) in adjacent neurectoderm. BF1 regulates development of the telencephalon (cerebral hemispheres) and regional specification within the prosencephalon (PR). Sonic hedgehog (SHH), secreted by the prechordal plate (P) and notochord (N), ventralizes the brain and induces expression of NKX2.1, which regulates development of the hypothalamus. Bone morphogenetic proteins 4 and 7, secreted by the adjacent nonneural ectoderm, control dorsal patterning of the brain. M, mesencephalon; R, rhombencephalon.

circumferential band anterior to the region of FGF-8 expression (Fig. 19.34). WNT1 interacts with EN1 and EN2 to regulate development of this region, including the cerebellum. In fact, WNT1 may assist in early specification of the midbrain area since it is expressed in this region at the neural plate stage. FGF-8 is also expressed at this early time in mesoderm underlying the midbrain-hindbrain junction and may therefore regulate WNT1 expression and initial patterning of this region. The constriction for the isthmus is slightly posterior to the actual midbrain-hindbrain junction, which lies at the caudal limit of OTX2 expression (Fig. 19.32).

Dorsoventral (mediolateral) patterning also occurs in the forebrain and midbrain areas. Ventral patterning is controlled by SHH just as it is throughout the remainder of the central nervous system. SHH, secreted by the prechordal plate, induces expression of NKX2.1, a homeodomain-containing gene that regulates

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