Genetic background modifies intestinal pseudo-obstruction and the expression of a reporter gene in Hox11L1-/- mice.
OBJECTIVE
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.
Parisi
Melissa A
MA
Department of Pediatrics, University of Washington School of Medicine, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NW, Seattle, WA 98105, USA.
Baldessari
Audrey E
AE
Iida
Malissa H K
MH
Clarke
Christine M
CM
Doggett
Barbara
B
Shirasawa
Senji
S
Kapur
Raj P
RP
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D002460:Cell Line; D005314:Embryonic and Fetal Development; D017615:Enteric Nervous System / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D017930:Genes, Reporter; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics*; D007421:Intestine, Small / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051379:Mice / Q000196:embryology / Q000235:genetics*; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D009474:Neurons / Q000378:metabolism; D019683:Penetrance; D014018:Tissue Distribution / Q000235:genetics; D014470:Umbilical Cord