The cell adhesion molecule l1 is required for chain migration of neural crest cells in the developing mouse gut.
OBJECTIVE
During development, the enteric nervous system is derived from neural crest cells that emigrate from the hindbrain, enter the foregut, and colonize the gut. Defects in neural crest migration can result in intestinal aganglionosis. Hirschsprung's disease (congenital aganglionosis) is a human condition in which enteric neurons are absent from the distal bowel. A number of clinical studies have implicated the cell adhesion molecule L1 in Hirschsprung's disease. We examined the role of L1 in the migration of neural crest cells through the developing mouse gut.


METHODS
A variety of in vitro and in vivo assays were used to examine: (1) the effect of L1 blocking antibodies or exogenous soluble L1 protein known to compromise L1 function on the rate of crest cell migration, (2) the effect of blocking L1 activity on the dynamic behavior of crest cells using time-lapse microscopy, and (3) whether the colonization of the gut by crest cells in L1-deficient mice differs from control mice.


RESULTS
We show that L1 is expressed by neural crest cells as they colonize the gut. Perturbation studies show that disrupting L1 activity retards neural crest migration and increases the number of solitary neural crest cells. L1-deficient mice show a small but significant reduction in neural crest cell migration at early developmental stages, but the entire gastrointestinal tract is colonized.


CONCLUSIONS
L1 is important for the migration of neural crest cells through the developing gut and is likely to be involved in the etiology of Hirschsprung's disease.
Anderson
Richard B
RB
Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Australia. rba@unimelb.edu.au
Turner
Kirsty N
KN
Nikonenko
Alexander G
AG
Hemperly
John
J
Schachner
Melitta
M
Young
Heather M
HM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D047108:Embryonic Development; D007422:Intestines / Q000196:embryology*; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008853:Microscopy / Q000379:methods; D039842:Neural Cell Adhesion Molecule L1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D000906:Antibodies; D039842:Neural Cell Adhesion Molecule L1; D045726:Metalloproteases