Disruption of hedgehog signaling reveals a novel role in intestinal morphogenesis and intestinal-specific lipid metabolism in mice.
OBJECTIVE
The hedgehog (hh) signaling pathway has been shown to play crucial roles in the development of embryonic gut. However, its role in intestinal development and function beyond the embryonic stage is still undefined.


METHODS
Expression of hh and its receptor, Patched, were examined by Western blot and X-gal staining. An anti-hh monoclonal antibody was administered into developing embryos or postnatal mice and histologic analyses were performed. Effects on lipid metabolism were examined by Oil Red O and Sudan III stainings, messenger RNA (mRNA) analysis, and electron microscopy. Serum apolipoprotein IV level, a marker for lipid absorption, was quantified by Western blot.


RESULTS
Mice receiving anti-hh monoclonal antibody in utero or after birth exhibited progressive runting and died before weaning. Histology revealed hyperproliferation of intestinal crypt epithelial cells and disorganization of the villi with prominent vacuolation and accumulation of neutral lipid. Fecal fat microscopy revealed numerous large fat droplets. Intestinal mRNA abundance of 2 candidate genes involved in lipid transport, mtp and apob, was unchanged, although serum levels of apolipoprotein A-IV were reduced.


CONCLUSIONS
Abnormal villus structure, lipid-filled enterocytes, and fatty stools in anti-hh monoclonal antibody-treated mice indicate a novel role for hh signaling in intestinal morphogenesis and lipid transport in postnatal mice.
Wang
Li Chun
LC
Department of Exploratory Science, Biogen Inc, Cambridge, Massachusetts 02142, USA.
Nassir
Fatiha
F
Liu
Zhong-Ying
ZY
Ling
Leona
L
Kuo
Frank
F
Crowell
Thomas
T
Olson
Dian
D
Davidson
Nicholas O
NO
Burkly
Linda C
LC
D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018938:Caco-2 Cells; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D020895:Enterocytes / Q000648:ultrastructure; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D015513:Oncogene Proteins / Q000235:genetics; D000072079:Patched Receptors; D011247:Pregnancy; D011506:Proteins; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology
D000911:Antibodies, Monoclonal; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D015534:Trans-Activators