Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass.
OBJECTIVE
Ectopic activation of hedgehog (HH) signalling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analysed the dose-dependent requirement of patched homologue 1 (PTCH1), a negative regulator of HH signalling on pancreatic development.


METHODS
We used a recessive spontaneous mutant mouse denoted as mes which carries a mutated Ptch1 resulting in deletion of the most carboxy-terminal cytoplasmic domain of the PTCH1 protein. In this study, we analysed pancreatic morphology in Ptch1 ( +/+ ), Ptch1 ( +/mes ), Ptch1 (+/-), Ptch1 ( mes/me ) (s) and Ptch1 (-/mes ) mouse embryos, as well as the islet mass in adult Ptch1 (+/+), Ptch1 (+/mes ) and Ptch1 (+/-) mice.


RESULTS
Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in any of the Ptch1 mutants. The levels of PDX1 and glucagon were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptch1 mutant mice. The beta, alpha and exocrine cell masses decreased at E18.5 in parallel with increased HH signalling, with beta cell mass showing the highest sensitivity to HH signalling with a significant decrease even in Ptch1 (+/mes ) mice. Adult Ptch1 (+/-) mice also showed a significant decrease in beta cell mass compared with wild-type mice.


CONCLUSIONS
Our findings indicate that the carboxy-terminal domain of Ptch1 is essential for pancreatic development. In addition, the loss of Ptch1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in HH signalling.
Nakayama
S
S
Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Arakawa
M
M
Uchida
T
T
Ogihara
T
T
Kanno
R
R
Ikeda
F
F
Azuma
K
K
Hirose
T
T
Kawamori
R
R
Fujitani
Y
Y
Watada
H
H
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface