Hip1r is expressed in gastric parietal cells and is required for tubulovesicle formation and cell survival in mice.
Huntingtin interacting protein 1 related (Hip1r) is an F-actin- and clathrin-binding protein involved in vesicular trafficking. In this study, we demonstrate that Hip1r is abundantly expressed in the gastric parietal cell, predominantly localizing with F-actin to canalicular membranes. Hip1r may provide a critical function in vivo, as demonstrated by extensive changes to parietal cells and the gastric epithelium in Hip1r-deficient mice. Electron microscopy revealed abnormal apical canalicular membranes and loss of tubulovesicles in mutant parietal cells, suggesting that Hip1r is necessary for the normal trafficking of these secretory membranes. Accordingly, acid secretory dynamics were altered in mutant parietal cells, with enhanced activation and acid trapping, as measured in isolated gastric glands. At the whole-organ level, gastric acidity was reduced in Hip1r-deficient mice, and the gastric mucosa was grossly transformed, with fewer parietal cells due to enhanced apoptotic cell death and glandular hypertrophy associated with cellular transformation. Hip1r-deficient mice had increased expression of the gastric growth factor gastrin, and mice mutant for both gastrin and Hip1r exhibited normalization of both proliferation and gland height. Taken together, these studies demonstrate that Hip1r plays a significant role in gastric physiology, mucosal architecture, and secretory membrane dynamics in parietal cells.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
Renu N
RN
Jain
Asma A
AA
Al-Menhali
Theresa M
TM
Keeley
Jianhua
J
Ren
Mohammed
M
El-Zaatari
Xunsheng
X
Chen
Juanita L
JL
Merchant
Theodora S
TS
Ross
Catherine S
CS
Chew
Linda C
LC
Samuelson
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019872:Chief Cells, Gastric / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005744:Gastric Acid / Q000378:metabolism; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005755:Gastrins / Q000097:blood / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D007437:Intrinsic Factor / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008854:Microscopy, Electron; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D011899:Ranitidine / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022142:Secretory Vesicles / Q000502:physiology* / Q000648:ultrastructure
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D005755:Gastrins; C489536:Hip1 protein, mouse; C489534:Hip1r protein, mouse; D008840:Microfilament Proteins; D044162:Parathyroid Hormone-Related Protein; D006632:Histamine; D011899:Ranitidine; D007437:Intrinsic Factor; D017506:H(+)-K(+)-Exchanging ATPase