The vertebrate nervous system is a major site of Hox gene expression and function. Studies on the patterns of expression, regulation and function of the vertebrate Hox gene family have played a key role in aiding our understanding of the basic ground plan of the CNS and processes that control how unique regional character is established and maintained in this complex organ system. This chapter will document the nature of the ordered patterns of Hox expression and link them with their regulation and functional roles in the nervous system.

Introduction

The adult vertebrate nervous system is a complex organ formed by a progressive series of intricately coordinated events that generate the components and circuitry essential for its function. While there is considerable diversity in the brain and CNS associated with higher order functions in vertebrates, underlying this final complexity there is a highly conserved basic genetic program that governs the fundamental patterns by which the central nervous system (CNS) is formed.

A central question is how this highly organized system arises in the body? For example, what ‘instructs’ a developing neuron to form in a particular location, correctly project to its targets or interact with other neurons? Part of the answer to these questions involves the products of the Hox transcription factor gene family that during development specify anterior-posterior (A-P) identity in different tissues, including the CNS. The purpose of this review is to highlight the expression, regulation and roles of Hox genes in patterning CNS development. A major focus will be placed on the hindbrain because of the considerable number of studies in different vertebrate models that demonstrate the important conserved role the Hox genes play in regulating the basic ground plan of this region of the CNS.

The Hox Gene Family

Initially identified and characterized in Drosophila as the genes associated with homeotic transformation, Hox genes were subsequently identified in vertebrates by virtue of their highly conserved homeobox sequences.^1-5 From a concerted effort of many different laboratories, a total of 39 Hox genes have been identified in most vertebrates, except the ray-finned fishes. This large gene family is organized into four separate chromosomal clusters that can contain up to 11 genes with each complex (Fig. 1).^5,6 Based on similarities between the putative translated sequences of the vertebrate Hox genes and the Drosophila Hox proteins, the Hox complex appear to have arisen by duplication and divergence from a common ancestor. The genes can be assigned into one of thirteen paralogous groups (Fig. 1). Thus, members of the labial (lab) subfamily, group 1 Hox genes, include Hoxa1, Hoxb1, and Hoxd1. Even though insect and vertebrates shared a common ancestor over hundreds of millions of year ago, their linear organization on the chromosome is maintain between complexes as well as conserved with the order found in Drosophila.^7,8 However, unlike the Drosophila Hox complex, the vertebrate complexes are small (˜120 kb) and devoid of nonHox genes. In ray-finned fishes there has been a subsequent round of genome-wide duplication, generating up to 8 Hox clusters and many more Hox genes.^9-12

Figure 1

The Drosophila and vertebrate Hox complexes. The Drosophila Hox Complex is split into two complexes: the Antennapedia Complex (ANT-C) and the Bithorax Complex (BX-C). In general, the vertebrate Hox genes are organized into four clusters found on separate (more...)

Regardless of the species, one of the most fascinating features of Hox genes is the phenomenon known as colinearity.^8,13-17 This term describes how the order in which each gene becomes activated matches their linear order along the chromosomal cluster. They are all transcribed in the same 5' to 3' orientation, with the 3' most genes expressed the earliest and with the most anterior borders of expression (Fig. 3). This process continues for each successive gene along the complex from the 3' to the 5' end. Consequently, the anterior borders of consecutively expressed genes are set more posteriorly than those of the earlier expressed genes, generating a nested and overlapping series of expression patterns. As a result of colinearity, unique combinations of Hox proteins are produced at different positions along the A-P axis of the developing embryo. This observation led to the proposal of a Hox Code whereby different combinations of Hox proteins generated by the nested domains of expression determine a cell's A-P placement and regional character within the developing hindbrain,^16,18,19 limb,^20-22 genitalia,²³ and somites of the embryonic trunk.^24,25

Figure 3

Hox proteins function as transcription factors to regulate other genes and hence play a pivotal role in the pathways that specify tissue identity. Each contains a homeodomain, translated from the sequence of the homeobox, which bears high amino acid sequence similarity to the homeodomain of the archetypical Hox member, Antennapedia. The homeodomain makes major groove contacts, via a helix-turn-helix motif, and minor groove contacts, via the N-terminal arm of the homeodomain, with DNA.²⁶ From numerous loss-of-function and gain-of-function experiments in diverse vertebrate and invertebrate species, it has been shown that the anterior border of a Hox gene expression domain is important as perturbations of this border typically result in homeotic transformations and malformations.^27,28 Here we review where these borders are set in the developing hindbrain of the CNS, what transcription factors and signaling pathways initiate the setting of these borders, and what are the consequences to CNS patterning when these borders are altered.

The Embryonic Vertebrate Nervous System

The central nervous system (CNS) begins as a thickened sheet of epithelial cells that forms the neural plate. Starting at the anterior end of the embryo, the lateral edges of the neural plate will roll upwards and fuse into the neural tube, while at the posterior end of the embryo the A-P axis is extended by cell proliferation, thereby elongating the trunk and neural plate. As the cells leave this proliferative region their A-P identity or regional character becomes determined. This process occurs in both the neural tube and the adjacent paraxial mesoderm as it differentiates into somites.

Since the development of the vertebrate embryo proceeds temporally in an anterior to posterior fashion, the rostral end of the embryo is more developmentally advanced than the caudal end. Following neural induction the neural tube becomes subdivided into morphologically distinct domains: the forebrain, midbrain, hindbrain, and spinal cord. Current models are consistent with the idea that the initial state of the neural tube is forebrain-like and that the more posterior regions (midbrain, hindbrain and spinal cord) arise through a progressive transformation to more posterior fates. This is referred to as the “activation and transformation” model of neural development.^29-31 It is believed that distinct signaling pathways and processes govern each of these territories rather than a single common mechanism.³²

The spinal cord can be further subdivided, according to the vertebra that will form to enclose it, into the cervical, thoracic, lumbar, and sacral domains. Within the cervical and thoracic domains, a third level of division can be identified as the brachial domain which spans vertebrae C5 to T1. These designations are important because different “columns” of MNs are generated in each domain. Hence in the brachial domain, the spinal cord will generate lateral column (LMC) neurons, whereas the remainder of the thoracic region will generate autonomic MNs.^a The LMC neurons will send axons into the limb, whereas the autonomic MNs will project axons to the body wall muscles.³³

Within a transverse cross section of the spinal cord, there are differences in the dorsal-ventral (D-V) axis as different cell layers can be distinguished (Fig. 2A,B). The inner most layer, which lines the lumen of the neural canal, is the ventricular layer. This is composed of undifferentiated, proliferating cells. It is surrounding by the gray-colored mantle layer which contains differentiating neurons. The mantle layer is enclosed by the white-colored marginal layer that contains the nerve fibers. The mantle layer can be further subdivided into the dorsal alar and ventral basal plates. The alar plate forms the sensory area while the basal plate forms the motor area of the spinal cord.

Figure 2

So far we have described all of the major components of the CNS, whereas the peripheral nervous system (PNS) will arise from the neural crest. The neural crest is a transitory population of cells that delaminate from the border area located between the surface ectoderm and the neural plate as the neural tube is formed. After their induction, they undergo an epithelial-to-mesenchymal transition and migrate to give rise to numerous derivatives.³⁴ In the head, the ‘first wave’ of neural crest migrate into the branchial arches while a ‘second wave’ migrates a short distance from the neural tube to form neural derivatives.

The brain stem is a relatively small region just anterior to the spinal cord, yet its functional significance is very great. The brain stem includes the midbrain and the hindbrain. The Hox genes are central to events involved in specifying the hindbrain territory³⁵ and furthermore they seem to be part of a highly conserved mechanism for regulating properties of this territory in vertebrates. During development, the vertebrate hindbrain undergoes a segmentation process which subdivides the neuroepithelium into a number of compartments or rhombomeres, along the anteroposterior (AP) axis.^32,36,37 Early cellular partitioning of the hindbrain into segments represents an important mechanism by which neuronal organization and diversification are initially established. The hindbrain is densely packed with vital structures. It contains the nuclei and fibers of the cranial nerves which innervate the muscles of the head and neck, transmit sensory information on hearing, balance and taste and control the cardio-vascular and gastrointestinal systems. In addition, it contains the sensory tracts ascending from the spinal cord to the thalamus and cortex and the motor pathways descending from the forebrain to the brain stem and spinal cord. The reticular formation of the rhombencephalon contains higher order relay centers that control respiration and blood pressure as well as centers that mediate arousal and wakefulness. The distinct neuronal groups in the hindbrain are also the major source of noradrenergic and serotonergic inputs to most parts of the brain. Brain stem patterning appears to use common cellular and molecular mechanisms to generate these features because they are a shared feature of vertebrates. To understand how patterns of neuronal connectivity are established and maintained, we first need to know how a given neuronal precursor comes to occupy its particular position in the nervous system, how it acquires a specific identity appropriate to that position, and how this translates into its specific differentiated properties.

Overt and Covert Segmentation of the Nervous System

In Drosophila, Hox gene expression is associated with the visible segmentation of the embryo.³⁸ Misexpression and mutational analysis of fly Hox genes result in the affected segments acquiring another segment's identity (homeotic transformation).⁵ One obvious example of segmentation in the vertebrate embryo is the formation of the somites from the paraxial mesoderm that will give rise to the axial skeleton, in addition to most of the musculature of the trunk. Early experiments with vertebrate Hox genes showed that their role in segmental identity was conserved when their loss or misexpression resulted in the transformation, and in some cases malformations, of elements of the axial skeleton.^24,25,39-47

A similar level of serial segmentation is seen in the hindbrain which visibly subdivides into a series of seven to eight compartments called rhombomeres (r).^32,36,37 Morphologically these compartments are short-lived, but each acts as a separate entity displaying very little cell mixing between adjacent compartments.^37,48 Even though each rhombomere will generate a similar pool of neurons, their number and axonal projections are rhombomere specific.^49,50 Patterns of expression in combination with extensive gain- and loss-of-function analyses in different vertebrates have revealed that the distinct cellular and molecular characteristics of rhombomeres are the result of different combinations of Hox genes being expressed in different rhombomeres; the so-called Hox Code.^16,19,51-70

Superficially the developing spinal column appears to lack the ordered pattern of segmentation that is displayed by the adjacent somites or by the hindbrain. Work with the chick neural tube suggests that it indeed lacks any form of direct segmentation^71,72 but that its local A-P character is probably determined by the adjacent somites hence there is some evidence for indirect segmentation through this route.^73-75 However, others argue that the symmetrical pattern of axonal projections along its length suggest that it displays some level of intrinsic segmentation. Regardless of the arguments of whether or not it is molecularly segmented, the adjacent somites as well as their sclerotome derivatives (the prevertebrae) are often been used as landmarks to position the anterior boundaries of Hox gene expression in the developing spinal column (Fig. 4).

Figure 4

Hox gene expression in the 12.5 dpc anterior-posterior (A-P) axis of the mouse spinal column. Hox genes from groups 5 to 13 begin their expression in the spinal column. Since the spinal column lacks overt segmentation, the adjacent somites (s) or prevertebrae (more...)

Hox Gene Expression in the CNS

Regulation of Neural Expression

Given that their temporal and spatial expression must be precisely controlled, the regulation of Hox gene expression is understandably complex. It can be broken down into three stages: (1) initiation, (2) establishment, and (3) maintenance. Many cis-acting elements that control the initiation and establishment of Hox gene expression have been identified.^27,109 The majority of these involve the regulation of the members from the first four paralog group because of interest in understanding how expression is regulated and coupled to hindbrain segmentation. Regulatory analyses have revealed that there are multiple rhombomeric enhancers that act as independent regulatory elements. They direct expression in specific-subsets of hindbrain segments and function outside of the Hox complexes on heterologous promoters linked to reporter genes.^82,110-129 A variety of other regulatory elements that mediate neural expression in other domains have also been found.^{89,92,112,116-118,129-137}

While these enhancers can display regulatory activity outside of the complex there is evidence that within a cluster some elements and Hox enhancers for other tissues may also be shared or competed for between adjacent genes.^{93,130,136,138-140} An interesting but open question is the extent to which these enhancers may work more globally within a complex. In addition to these local transcriptional control elements, Hox expression can be controlled post-transcriptionally by the recently discovered Hox specific miRNAs.^141,142

Expression and Neuronal Phenotypes

The majority of Hox loss-of-function and gain-of-function studies describe the effects that these mutations have on axial and limb skeleton patterning and formation. In terms of what effects these mutations have on CNS development, more work has been produced looking at the defects in the organization of the hindbrain and its cranial nerves; whereas, a smaller body of work deals with the alterations and deletions of the MNs projecting from the spinal column into the limbs or trunk.

In the hindbrain targeted inactivation of the Hoxa1 gene results in loss of r5 and reduction in the size of r4.^65,256 However, the loss of Hoxb1 function is mild in comparison. Initially r4 character is triggered but it is not maintained and there is a transformation to an r2-like character. ^69,257 The generation of compound group 1 mutants leads to more severe phenotypes. Hence in Hoxa1 and Hoxb1 double homozygous mutants r4 and r5 fail to be specified and are missing along with derivatives of the second branchial arch which are generated from neural crest cells that migrate from r4.^61,67,70 As a consequence of their gain or loss of expression in the hindbrain, Hoxb1 and Hoxa1 affect the projections of the cranial MNs from the hindbrain.^{59,60,66,69,258} These studies have shown that Hoxb1 is essential for the formation, migration and projections of the facial MN.^{59,69,257,259} Studies with the Hoxa1, Hoxb1 and Hoxb2 mutants also show later effects of these genes on neurogenesis.^68,260 Similar work with group 3 paralogs have highlighted their important role in the formation of the abducens and hypoglossal neurons.^63,261

Forcing expression of Hox genes in more anterior domains of the hindbrain typically leads to rhombomere transformations. Ectopic expression of Hoxa1 results in transformation of r2 into r4,^56,60 and similar results are produced when Hoxa1 and Hoxb1 expression is anteriorized in the hindbrain by excess RA treatment.^206,217 These changes in rhombomere identity have profound effects on the subsequently formed CNS structures, such as the cerebellum that is derived primarily from r1.²⁶² Loss of Hoxa2 causes a caudal expansion of the cerebellum,⁶⁶ which is further extended into r2 and r3 territory when both paralogous Hoxa2 and Hoxb2 are absent.²⁶⁰

The products of Hox genes also determine the axonal projection patterns from the spinal column. Targeted inactivation of HoxA, HoxC and HoxD genes results in alterations and/or reductions of the MNs axonal projections to muscle targets in the limbs.^97-100,263 In general, members from groups 6 and 8 are important for specifying brachial MNs that innervate the forelimbs whereas members from groups 9, 10 and 11 have been shown to control MN projections into the hindlimbs. Interestingly, mutation of the Hoxb13 gene does not produce rearrangements or deletions of elements derived from the CNS but results in the overgrowth of the posterior spinal cord and tail vertebrae.²⁶⁴ This suggests that, unlike the other Abd-B like Hox proteins, Hoxb13 functions as a repressor of neuronal and caudal vertebral proliferation.

Studies in which the gene is mis-expressed in the target area, or in tissue through which the neurons project, have highlighted the importance of coordinating the simultaneous expression of these genes in both the paraxial mesoderm and neuroectoderm. Viral misexpression of Hoxc6 in the chick cervical paraxial mesoderm disrupts the spinal nerve's projection, causing it to prematurely halt is migration.¹⁰² This suggests that the signals from the mesoderm through which the axon migrates are important to direct their outgrowth.¹⁰² Similarly, the viral misexpression of Hoxb1 in the first branchial arches causes Hoxb1-specified neurons to alter their migration patterns so that they project axons into the first branchial arch rather than their normal targets located in the second branchial arch.⁵⁹ This link between the local A-P character of the neural tube and the flanking mesoderm tissue is missed in gene-targeting experiments because such experiments eliminated the targeted gene's product from both compartments.

The Roles of Auto- and Cross-Regulatory Interactions between Hox Genes

An important consideration in both the regulation and function of Hox genes in the nervous system is the degree to which they cross-regulate each other. A common feature from the cis-regulatory studies on segmental expression of Hox genes in the hindbrain is that early signals (RA, FGFs) and transcription factors (kreisler, Krox20) are transient. Hence, other mechanisms are required to maintain or stabilize their domains of expression critical for later expression and function in rhombomeric segments. By analogy to Drosophila, mechanisms involving Polycomb and trithorax mediated epigenetic changes in chromatin, have been widely postulated to be important in vertebrate Hox regulation. In support of this, mouse mutants for members of the PcG and trxG have been shown to alter Hox expression, primarily examined in the mesoderm due to the prevalence of skeletal defects.²⁶⁵ However, the regulatory analyses of rhombomeric enhancers has uncovered a surprising degree of auto and cross-regulation between the Hox genes themselves, as an important mechanism for maintaining segmentally-restricted expression.^{70,82,110,116,122,123,140,266-268} During the establishment and maintenance stages, Hox proteins can directly cross-regulate the expression of other Hox genes,^{82,122,140,269-271} or perpetuate their own expression through auto-regulatory elements.^{82,110,267,271} Hence, following initiation by transiently expressed upstream factors or signals, Hox response elements serve to generate feedback loops that stabilize and perpetuate segmental expression. These lock-down or feedback loops have important implications in functional studies because mutation of one Hox gene can alter the regulation of other family members, generating a more complex phenotype.

One of the best examples of such loops from regulatory and mutant analyses relates to rhombomere 4. It appears that there is a pathway for specifying r4 character and later neuronal identities dependent upon cross-talk between Hox genes.²⁶⁸ Early retinoid signaling triggers both Hoxb1 and Hoxa1 expression directly via RAREs located at the 3' end of these genes.^{56,112,217,227} In combination with Pbx and Prep/Meis cofactors, both Hoxa1 and Hoxb1 then bind to the auto-regulatory enhancer of Hoxb1 to maintain its expression. ^110,272-278 Hoxb1 in turn directly cross regulates both Hoxb2 and Hoxa2 specific expression in r4 and Hoxb2 feedbacks upon Hoxb1 to support its expression.^{110,112,122,123,268} By these loops it is clear that Hoxb1 plays a central role in specifying and maintaining r4 identity and the mutation of any of the individual Hox genes in this these cross-talk loops directly correlates with the neuronal phenotypes observed.²⁶⁸

Further evidence for the importance of these feedback loops in other vertebrates is provided by loss and gain-of-function experiments in zebrafish where Hox, Pbx and Meis mutations all show primary defects in hindbrain patterning and alterations of Hox expression.^{51,55,58,279-283} There is also emerging evidence that both positive and negative feedback loops among Hox genes is important in the spinal cord.^33,96

In conclusion, regulatory analyses seeking to understand the cis-regulation of Hox genes themselves and the upstream cascade have surprisingly provided novel insight into potential Hox target genes. By identifying a series of known in vivo relevant target elements it will be possible to define the cis-regulatory code of a Hox response element and use it to predict down-stream target genes identified by genomic and microarray analysis. Therefore, a major area of interest in future Hox research will be to understand how different Hox proteins bindtheir target sites, what cofactors they use and how the output of activation or repression is achieved. This will be important in predicting and understanding their interactions on down-stream target genes. This work should also be highly relevant to Hox gene expression, regulation and function in tissues outside the nervous system.

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Footnotes

a

In the chick the autonomic MNs are called the Column of Terni neurons.

b

These borders differences are highlighted in Figure 4 by the presence of a red rectangle.

c

In the mouse, these are Cdx1, Cdx2, and Cdx4. The chicken and Xenopus orthologs are CdxA, CdxB, and CdxC; and Xcad1, Xcad2, and Xcad3, respectively.