450 REVIEW Gut: first published as 10.1136/gut.51.3.450 on 1 September 2002. Downloaded from Homeobox genes in gut development F Beck ............................................................................................................................. Gut 2002;51:450–454 Classical descriptions of gut development specify by the Hox1 system consisting of four clusters, subdivision into foregut, midgut, and hindgut together Hox-a, Hox-b, Hox-c, and Hox-d, that appear to have arisen by a two step reduplication from an with their derivatives. This is based on the anatomical ancestral complex common to mammals and localisation of the anterior and posterior intestinal flies.2 There are 13 potential gene sites on each cluster but none contain a gene at every potential portals separating the roof of the yolk sac from the locus (fig 1). Patterns of gene expression in foregut and hindgut diverticulae. When considering the paraxial and lateral plate mesoderm, neural tube, molecular basis of intestinal differentiation, it is neural crest, hindbrain, and branchial arches demonstrate that spatial colinearity is main- necessary to think in terms of the genes involved, and in tained; in addition, the relative timing of gene this respect those containing the homeobox motif are expression in a craniocaudal direction also important players in specifying the fate of both the reflects the order of the genes on the chromosome (temporal colinearity).3 endodermal and mesodermal components of the gut. In Apart from the Hox clusters, many so-called this review, evidence is considered for their role, with “dispersed” homeobox genes exist in mice and humans. It is probable that these arise by redupli- particular regard to the acquisition of positional cations that have been transposed away from the information. Hox cluster and often perform functions other .......................................................................... than or additional to coding for positional information. Some form a so-called Para-Hox cluster4 which is thought to be an ancient ells which make up a multicellular organ- paralogue of the Hox cluster—both having arisen ism are subject to constraints that are not from a putative ancestral Proto-Hox cluster. Para- Cimposed upon their protozoan counter- Hox genes exhibit colinearity in neural tube and parts. In addition to coding for proteins con- gut endoderm where they also seem to be associ- cerned with structural and narrowly functional ated with craniocaudal patterning. In mammals, http://gut.bmj.com/ properties, the DNA of these cells must include the cluster consists of Gsh1, Pdx1, and Cdx2 but genes that impart positional information. This possibly others await definition. makes possible the complex cell movements that are required for the assumption of form and HOMEOBOX GENE EXPRESSION IN THE allows diverse temporally regulated interactions GUT between shifting populations of cells to take Genes belonging to the Hox cluster are expressed place. The latter are necessary for the inductive in a colinear manner along the length of the processes which occur as the organism increases lateral plate mesodermal component of the gut on September 26, 2021 by guest. Protected copyright. in complexity and result in the hierarchical during development.5 Deschamp et al describe expression of genes regulating cellular differen- three stages of Hox gene expression in the tiation. The basic mechanisms involved are well 3 illustrated in Drosophila because, compared with mouse. The process is initiated in the posterior higher chordates, this invertebrate retains much part of the primitive streak in late streak stage of the segmental pattern of more primitive embryos. Expression then spreads anteriorly in organisms. Thus the definitive anteroposterior sequence for individual Hox genes to involve the pattern of the fly is achieved in stages. Initially, cells in the anterior part of the streak and genes of maternal origin transcribe mRNA Hensen’s node. This extension is not due to clonal sequestered in the cytoplasm of the ovum. This is expansion but takes the form of a spreading followed by the sequential action of segmentation wave. As the expression domains of various Hox genes known as gap genes, pair rule genes, and genes “arrive” at the anterior region of the streak segmental polarity genes. These establish seg- at different times, this results in linear expression mental periodicity while the identity of individual of positional information along the anteroposte- segments is specified by homeotic selector genes. rior axis as well as in the components of the lateral plate mesoderm which make up the meso- ....................... The latter are examples of a much larger group of genes containing a conserved “homeobox” se- dermal tissues of the gut and associated viscera. Correspondence to: quence coding for a DNA binding homeodomain Thereafter, further expression of Hox genes is Professor F Beck, and thus active as transcription factors. Those clonally transmitted by the progeny of cells origi- Biochemistry Department, nating in the streak. Finally, mechanisms that Adrian Building, University that are concerned with axial patterning are clus- of Leicester, University Rd, tered in the HOM-C complex and exhibit spatial maintain and in a sense “lock in” homeobox gene Leicester LE1 7RH, UK; colinearity—that is, the sites of gene expression expression become operative to ensure continued [email protected] along the body axis reflect the relative chromo- spatial fidelity of expression. In Drosophila, the polycomb, trithorax, and brahma group of genes Accepted for publication somal order of the genes. The HOM-C complex 7 November 2001 has its counterpart in all higher species. In mam- serve this purpose and their homologues have ....................... mals, exemplified by the mouse, it is represented been identified in vertebrates. www.gutjnl.com Homeobox genes in gut development 451 Figure 1 Diagrammatic representation of the HOM-C lab pb Dfd Scr Antp Ubx abdA AbdB Drosophila complex in Drosophila and its Gut: first published as 10.1136/gut.51.3.450 on 1 September 2002. Downloaded from HOM-C phylogenetic homology in the form of four Hox paralogues. Mouse Hox-a a-1 a-2 a-3 a-4 a-5 a-6 a-7 a-9 a-10 a-11 a-13 evx-1 Hox-b b-1 b-2 b-3 b-4 b-5 b-6 b-7 b-8 b-9 Hox-c c-4 c-5 c-6 c-8 c-9 c-10 c-11 c-12 c-13 Hox-d d-1 d-3 d-4 d-8 d-9 d-10 d-11 d-12 d-13 evx-2 Paralogous 1 2 3 654 13121110987 subgroups Anterior 3¢ 5¢ Posterior Dispersed homeobox genes belonging to the Nkx group are the posterior segments; an extended function in vertebrates also differentially expressed in specific mesodermal regions of may be connected to the fact that the genes of maternal origin the gut. As yet the picture is not clear and may vary between and the segmentation genes (see above) are not greatly species but it has been suggested that they influence epithelial involved in axial specification and a greater role for Cdx2 in growth and differentiation through target genes coding for regulating Hox gene expression is thus conceivable. From day secreted growth factors such as those of the BMP family.6 12 of mouse gestation, Cdx2 expression is confined to the intestinal epithelium (fig 2) from a region just rostral to the “Genes belonging to the Hox cluster are expressed in a hepatic diverticulum to the distal colon. In the adult, high lev- colinear manner along the length of the lateral plate els of expression persist in the proximal colon gradually mesodermal component of the gut during development” falling off in the ileum and jejunum cranially and in the distal colon caudally. The function of Cdx2 during development and http://gut.bmj.com/ Although Hox and Nkx genes are strongly expressed in in the adult is discussed below. intestinal mesoderm during development, they do not feature Two other Caudal homologues exist in vertebrates. In the prominently in the endodermal layer caudal to the stomach mouse these are Cdx1 and Cdx4. They are not linked to the mucosa. There are a few exceptions, principally involving the Para-Hox cluster but both are expressed in gut endoderm. Cdx1 is demonstrable in the primitive streak and at other sites endoderm of the cloacal region where Hoxd13 (as well as during early mouse development11 and has been shown to play Hoxa13 in the chick) is expressed in the endoderm as well as in a role in axial specification.12 However, it is not seen in gut the underlying mesoderm, possibly in response to Sonic hedge- endoderm until day 15.13 14 It is upregulated when develop- on September 26, 2021 by guest. Protected copyright. hog. There is also report of Hoxa 8 expression in the small and 13 mental maturation of the gut occurs. In the adult it is princi- large intestinal endoderm while numerous Hox genes are pally expressed in the intestinal crypts and it is possible that it expressed in the endodermal layers of the stomach and is principally concerned with maturation of the stem cells in oesophagus. Accounts of Hox gene expression sites in the gut 7 the intestine although no gut phenotype has been described in are summarised by Sekimoto and colleagues and by Beck and null mutant mice. colleagues.5 By contrast, two members of the Para-Hox group are strongly transcribed and translated in the postgastric intestinal epithelium during the greater part of gestation and in the adult mouse. Pdx1 expression8 begins at 8.5 days of ges- tation in the dorsal cells of the gut. At nine days it is restricted to the presumptive duodenal region and to the cells of the dorsal (and later also the ventral) pancreatic bud. By 13.5 days virtually all of the endodermal components of the pancreatic duct and the pancreatic primordial produce Pdx1 but as development proceeds gene expression is largely restricted to the beta cells of the endocrine pancreas and to the epithelium of the duodenal villi.