Structural abnormalities associated with congenital megacolon in transgenic mice that overexpress the Hoxa‐4 gene

Abstract

Congenital megacolon develops in transgenic mice that overexpress the homeobox-containing gene, Hoxu-4. The current study was done to identify abnormalities of the terminal colon that might account for the phenotype. The terminal bowel of transgenic mice was compared with that of control and lethal spotted (ZslZs) mice, a strain in which megacolon also develops. The terminal colon of the transgenic mice contained fewer ganglia than that of controls, but was hypoganglionic, rather than aganglionic like that of ZslZs mice. The neurons present in the adult transgenic colon were significantly increased in size and a subset of very large neurons (>40 p. m in maximum diameter) were observed. Electron microscopic studies of young adult transgenic mice revealed that the ganglia and nerves of the myenteric plexus had the ultrastructure of extraenteric peripheral nerve rather than that of the enteric nervous system (ENS). The myenteric ganglia in the transgenic animals contained Schwann cells associated with a basal lamina that enveloped axons completely and individually, instead of glia. Although collagen is excluded from the ganglia and thin nerve fibers of the normal ENS, a collagen-containing endoneurium surrounded each of the axon-Schwann cell units of the abnormal nerve fibers of the transgenic colon. Some of the neurons of the transgenic mice were located in these nerve bundles rather than in ganglia. There were also smooth muscle abnormalities in the terminal bowel of the transgenic mice. Wide gaps were present in the longitudinal muscle of the transgenic mice; these gaps contained ganglia that were in contact with the adventitia. These longitudinal smooth muscle cells were more irregular than those of controls and they contained fewer puncta adherens; moreover, a larger proportion of the volume of the cytoplasm of transgenic smooth muscle cells was occupied by organelles. Finally, an extensive thickening and reduplication of the basal lamina surrounding the smooth muscle cells of the muscularis mucosa was observed in the transgenic colon and resembled 0 1993 WILEY-LISS, INC.that found in ZslZs mice. These data suggest that both smooth muscle and the innervation of the terminal bowel of neonatal Hoxu-4 transgenic mice are structurally abnormal. Although some of the abnormalities seen in Hoxu-4 transgenic mice are similar to those which arise in Zslls mice, the two conditions are not identical. In both animals, the data are consistent with the hypothesis that the defects arise as a result of a defective interaction between the precursors of enteric neurons and smooth muscle. o 1993 Wiley-Liss, Inc.

Antero-posterior patterning of the vertebrate digestive tract: 40 years after Nicole Le Douarin's PhD thesis

“…The anterior expression limits of Hox genes in the endoderm do not always correlate with boundaries between organs but there are hotspots of Hox boundaries at the levels of sphincters (pyloric, ileocaecal, anal) (Roberts, 2000). Hox gene inactivation may lead to digestive tract malformations as reported for Hoxa3 (Manley and Capecchi, 1995, Manley and Capecchi, 1998), Hoxa5 (Aubin et al, 1999, Aubin et al, 2002, Aubin et al, 1997), Hoxc4 (Boulet and Capecchi, 1996, Hoxa13 and Hoxd13 (Warot et al, 1997) and Hoxa4 (Tennyson et al, 1993, Tennyson et al, 1998. Their inactivation does generally not result in homeotic transformations, possibly due to redundancy although redundancy does not preclude from observing homeotic transformations of vertebrae in the mesoderm.…”

“…Among experimental anterior expansions of Hox gene expression, only that of Hoxa13 in the mesenchyme leads to induction of hingut fate in the midgut (Roberts et al, 1998). Others induce malformations rather than posterior transformations (Pollock et al, 1992, Tennyson et al, 1993, Tennyson et al, 1998. There is only one example of Hox gene playing a direct role in endoderm which concerns Hoxa13 in the hindgut (de Santa Barbara and Roberts, 2002).…”

Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease

“…In HOX genes, HOXA4 transgenic mice develops congenital megacolon [28], while HOXB5 are correlated with the migration and differentiation of NCCs, suggesting a regulatory role of HOXB5 in the development of NCCs [29]. What is more, perturbation of HOXB5 signaling in NCC from the entire neural tube causes apoptosis and neurocristopathies in mice [30].…”

Intestinal Motility Disorders and Development of the Enteric Nervous System

“…Neonatal hoxa-4 transgenic mice exhibit a short segment of hypoganglionic terminal colon. In addition, the ganglia that are present are abnormally located (88,89). Because this is a gain-of-function transgenic study, it is difficult to infer from these studies the physiologic roles of hoxa-4 in normal ENS development.…”

“…These transgenic mice overexpress hoxa-4 and also show some ectopic expression in that the transgene is expressed in mesenchyme throughout the bowel (87). (88).…”