Genetic background modifies intestinal pseudo-obstruction and the expression of a reporter gene in Hox11L1-/- mice.

Background & Aims: The transcription factor Hox11L1 is expressed by enteric neurons. Two groups mutated murine Hox11L1, and reported lethal intestinal pseudo-obstruction and colonic hyperganglionosis in many, but not all, homozygous null mutants. We investigated the regulation of Hox11L1 and factors that influence the penetrance of pseudo-obstruction in Hox11L1-null mice.

Methods: Expression of beta-galactosidase (lacZ), under control of putative Hox11L1 regulatory sequences, was assessed in transgenic mice wild-type, heterozygous, and null for native Hox11L1. Transgene expression and signs of pseudo-obstruction were compared in null mice with different genetic backgrounds.

Results: In enteric neurons and other parts of the nervous system, the transgene was expressed in a pattern consistent with native Hox11L1. Enteric beta-galactosidase activity initiated in the proximal small intestine and spread cranially and caudally in a subset of postmitotic enteric neurons. Hox11L1-lacZ transgene expression persisted in Hox11L1-null animals, suggesting that Hox11L1 is not required cell autonomously for neuronal survival. Genetic background dramatically affected the phenotypes of Hox11L1-null animals, with complete penetrance of severe proximal colonic distention on a predominantly C57BL/6J (B6) background and very low penetrance of dysmotility on a 129SvJ (129) background. Coincidently, Hox11L1-lacZ expression by most enteric neurons, but not CNS neurons, was lost on a 129 background.

Conclusions: Cis-acting, 5' regulatory elements are sufficient to regulate site-specific expression of Hox11L1 in vivo. Expression of the transgene by enteric neurons and penetrance of pseudo-obstruction in Hox11L1-null animals are influenced by one or more modifier genes, counterparts of which may play a similar role in human disease.