Immature enteric neurons in Ncx/Hox11L.1 deficient intestinal neuronal dysplasia model mice.
OBJECTIVE
The Ncx/Hox11L.1 gene is required for adequate development of enteric neurons in mice and Ncx/Hox11L.1 deficient (Ncx-/-) mice are used as a model for human intestinal neuronal dysplasia (IND) because of similar histopathology (hyperganglionosis), however, some 50% of Ncx-/- mice develop megacolon with a caliber change in the proximal colon, and die when 21-35 days old. We used polysialylated neural cell adhesion molecule (PSA-NCAM) to examine the maturity of enteric neurons in Ncx-/- mice to further understand the etiology of IND.


METHODS
PSA-NCAM immunoreactivity was measured in specimens taken 1 cm proximal to the ileocecal valve (ileum), 1 cm distal to the ileocecal valve (proximal colon), and 1 cm proximal to the anus (distal colon) from 63 mice (Ncx-/-: n = 14, Ncx+/-: n = 30, and Ncx+/+: n = 19) on days 14 (D14), 21 (D21), and 27 or later (>D27).


RESULTS
PSA-NCAM was positive (indicating immaturity) in proximal colon (submucosal and myenteric plexuses) from 8/14 (57%) Ncx-/- mice (2/4 on D14, 4/6 on D21, and 2/4 on >D27) and from 5/30 (17%) Ncx+/- mice (0/2 in D14, 2/13 in D21, and 3/15 in >D27). PSA-NCAM was negative (indicating maturity) in all other specimens. The incidence of PSA-NCAM positive neurons in Ncx-/- appeared to be correlated with the mortality rate seen in IND mice.


CONCLUSIONS
Our data suggest that colonic dysmotility and pathology seen in Ncx-/- mice may be due to persistence of immature neurons in the proximal colon, which could also be the case in human IND and warrants further investigation.
Kato
Yoshifumi
Y
Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. ykato@juntendo.ac.jp
Miyahara
Katsumi
K
Hatano
Masahiko
M
Hasegawa
Yuta
Y
Seki
Tatsunori
T
Frykman
Philip K
PK
Kusafuka
Junichi
J
Lane
Geoffrey J
GJ
Yamataka
Atsuyuki
A
D000818:Animals; D018398:Homeodomain Proteins / Q000235:genetics*; D007422:Intestines / Q000294:innervation* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology*
D018398:Homeodomain Proteins; C107836:Tlx2 protein, mouse
J Clin Invest. 1997 Aug 15;100(4):795-801
9259577
J Cell Biochem. 1998 Sep 1;70(3):304-12
9706867
J Neurosci. 1995 Dec;15(12):8310-9
8613764
J Neurosci Res. 2002 Nov 1;70(3):327-34
12391592
Pediatr Surg Int. 2007 Oct;23(10):991-5
17684751
J Pediatr Surg. 2007 Jun;42(6):1081-8
17560225
Nat Med. 1997 Jun;3(6):646-50
9176491
J Pediatr Surg. 2001 Aug;36(8):1293-6
11479879
Anat Embryol (Berl). 1991;184(4):395-401
1952111