Fetal development of the enteric nervous system of transgenic mice that overexpress theHoxa-4 gene

Abstract

Megacolon occurs in neonatal and adult transgenic mice that overexpress the Hoxa‐4 gene. Abnormalities, which are restricted to the terminal colon of these mice, include a hypoganglionosis, abnormal enteric ganglia with a structure appropriate for extra‐enteric peripheral nerve and not the enteric nervous system (ENS), and gaps in the longitudinal muscle occupied by ganglia. To investigate the developmental origin of these abnormalities, we analyzed the development of the pelvis and terminal colon in Hoxa‐4 transgenic mice. Morphological abnormalities were detected as early as E13. These included an enlargement of the mucosa and the bowel wall, a thickening of the enteric mesenchyme, and the ectopic location of pelvic ganglion cells, which initially clustered on the dorsolateral wall of the hindgut. As the bowel enlarged, these ectopic cells become ventrolateral and, between days E17 and E18.5, appeared to become incorporated into the gut, leaving neuron‐filled gaps in the longitudinal muscle layer. The ectopic ganglia retained extra‐enteric characteristics, including the presence of capillaries, basal laminae, collagen fibers, and catecholaminergic neurons, even after their incorporation into the bowel. It is proposed that the abnormal and ectopic expression of the Hoxa‐4 transgene in the colon causes signalling molecule(s) of the enteric mesenchyme to be overproduced and that the overabundance of these signals leads to mucosal enlargement and misdirection of migrating pelvic neuronal progenitors. Dev. Dyn. 1998;211:269–291. © 1998 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).…”

Enteric nervous system development: Analysis of the selective developmental potentialities of vagal and sacral neural crest cells using quail-chick chimeras

“…However, the situation is likely to be more complex. It is now well documented that numerous genes, cell lineages, and signalling pathways are involved in the development of the ENS (Tennyson et al, 1998;Wartiovaara et al, 1998; for reviews see Gershon, 1997Gershon, , 1998Gershon, , 1999Taraviras and Pachnis, 1999). Knockout or spontaneous mutations of a number of genes including endothelin-3 (ET-3), the ligand for endothelin receptor-B (EDNRB), or GDNF and its functional receptor RET, cause a loss of enteric neurons and glia within variable lengths of the gut Hosoda et al, 1994;Schuchardt et al, 1994;Pichel et al, 1996;Sanchez et al, 1996).…”

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.…”