Rhombomeres and Longitudinal Patterning

The rhombomeres are transient subdivisions that were described in the embryos of a number of species including the human starting in the late 1800s. Their analysis underwent a dramatic renaissance nearly 100 years later with the application ofmodern cellular and molecular techniques, spearheaded by the efforts of Andrew Lumsden and colleagues.

As many as eight rhombomeres have been described, and these are denoted r1, r2, r3, and so on from rostral to caudal (Fig. 3). The second through sixth rhombomeres (r2-r6) are similar in length and readily visible in most species. The first and last two rhombo-meres may represent transitional neuromeres at the junctions between hindbrain and mesencephalon and hindbrain and spinal cord.

Rhombomere boundaries have several features that contribute to a physical segmentation of the hindbrain neural tube. The proliferation rate is lower at the boundaries, creating the indentations that mark their positions visibly. The pattern of intercellular communication via gap junctions is modulated at the boundaries, several extracellular proteins are preferentially expressed there, and cells in alternating rhombomeres have different cell adhesion properties such that they tend to segregate if mixed. All of this contributes to the formation of a physical barrier to cell movement over rhombomere boundaries. Indeed, in contrast to the extensive circumferential migration that occurs among certain hindbrain neuron populations, rostrocaudal migration is much more limited. This has led to the idea that the rhombomeres compartmentalize the hindbrain, confining progenitor cells and their offspring to specific rostrocaudal domains. Of course, longitudinal fibers penetrate the rhombomere boundaries, and some neuron populations breach the barriers as well, especially at sites of intersection by fiber tracts.

The rhombomeres appear during a period when many hindbrain neurons are being generated, and they fade away by the time most of the major nuclei of the hindbrain have appeared. The temporal concurrence with neurogenesis and differentiation suggests that the rhombomeres play a role in patterning that differentiation. Molecular correlates of rhombomeric com-partmentalization strongly support this notion. In particular, the rhombomeric domains are correlated with the expression of a number of developmental regulatory genes that are involved in controlling the differentiation of neurons into specific phenotypes along the rostrocaudal axis.

One class of regulatory genes that figures prominently is the Hox gene family, which encodes transcription factors whose differential expression establishes regional patterns of differentiation in a variety of organisms and organ systems. Hox genes are ordered in a specific sequence within the genome, a relationship that is reiterated in their tissue expression pattern. Within the hindbrain, Hox genes have a sequentially overlapping pattern of expression that is strongly correlated with the rhombomeres and provides each of them with a unique combinatorial address (Fig. 6). Evidence that the Hox genes are important determinants of neuronal differentiation comes from a variety of manipulations that alter the pattern of Hox gene expression. These include transgenic knockouts of specific Hox genes, ectopic expression of Hox genes by retroviral gene transfer, heterotopic transplantation of rhombomeres, treatment with retinoids, perturbations of Hox gene promoter sequences that alter the region-specific expression pattern, and manipulation of other genes that regulate Hox gene expression. In parallel with alterations in Hox gene expression, these manipulations lead to changes in the regional pattern of neuronal differentiation, such that neuronal phenotypes

Figure 6 The relationship of rhombomeric domains to the longitudinal expression patterns of Hox genes in the mouse hindbrain. Black indicates strong expression, and gray indicates weaker expression (reproduced with permission from Keynes and Krumlauf, Annual Review of Neuroscience, Vol. 17, © 1994 by Annual Reviews, www.AnnualReviews.org).

Figure 6 The relationship of rhombomeric domains to the longitudinal expression patterns of Hox genes in the mouse hindbrain. Black indicates strong expression, and gray indicates weaker expression (reproduced with permission from Keynes and Krumlauf, Annual Review of Neuroscience, Vol. 17, © 1994 by Annual Reviews, www.AnnualReviews.org).

characteristic of a given rhombomere appear in a different rhombomere.

Hox genes are also expressed by the emigrating cranial neural crest cells and are involved in patterning the various mesenchymal derivatives of the cranium, branchial arches, and neural crest-derived thoracic structures.

How is the normal, longitudinally sequential pattern of Hox gene expression established? This appears to be a complicated issue that involves a number of factors. Hox gene expression is known to be regulated by retinoids, acting through nuclear retinoid receptors, which are ligand-dependent transcription factors that interact directly with Hox gene promoter sequences. This regulation is concentration dependent. Since retinoid synthesis has been shown to be high in the spinal cord but very low in the hindbrain, a diffusion gradient of retinoids from the spinal cord rostrally into the hindbrain could contribute to setting up the pattern. Hox gene expression is also regulated by the action of other transcription factors via specific promoter sequences that direct expression differentially according to tissue type and region. The pattern of expression of such transcription factors is therefore pivotal in setting up the pattern. Lastly, Hox gene expression is cross-regulated and autoregulated by Hox proteins, in cooperation with other transcription factors. An important feature that underscores the complexity of Hox gene regulation is the dynamic pattern of expression in the hindbrain. Hox genes do not merely pop up in specific longitudinal domains but may be expressed in broader domains that eventually become restricted and that are modulated over time also in the transverse plane.

The Hox genes are not the only genes that exhibit rhombomere-related patterns of expression, but they are the most extensively studied so far with respect to a role in regulating neuronal differentiation. Some of the other rhombomere-related genes are likely to be downstream targets of the Hox genes because they code for membrane receptors and signaling molecules that are involved in features of differentiation, such as directed cell migration and axonal outgrowth. Others, such as the kreisler and Krox-20 genes, are also transcription factor genes that participate with the Hox genes in the network of gene activity that sets up the regional patterning of the hindbrain.

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