Loss of neurons in the hippocampus and cerebral cortex of AMSH-deficient mice.
AMSH, a molecule that associates with STAM1, is involved in the in vitro cell growth signaling mediated by interleukin 2 and granulocyte-macrophage colony-stimulating factor. To investigate the in vivo functional role of AMSH, we have generated AMSH-deficient mice by gene targeting. The AMSH-deficient mice were morphologically indistinguishable from their littermates at birth, and histopathological examinations revealed normal morphogenesis in all tissues tested. However, all the AMSH-deficient mice exhibited postnatal growth retardation and died between postnatal day 19 (P19) and P23. Examination of brain sections at P6 demonstrated significant loss of neurons and apoptotic cells in the CA1 subfield of the hippocampus. Brain atrophy developed by P16 and was accompanied by complete loss of the CA1 neurons in the hippocampus and marked atrophy of the cerebral cortex. Furthermore, AMSH-deficient hippocampal neuronal cells were unable to survive in vitro, even in the presence of several stimulatory cytokines, while AMSH-deficient cerebellar neurons, thymocytes, and embryonic fibroblasts survived normally. Taken together, these observations indicate that AMSH is an essential molecule for the survival of neuronal cells in early postnatal mice.
Ishii
N
N
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan.
Owada
Y
Y
Yamada
M
M
Miura
S
S
Murata
K
K
Asao
H
H
Kondo
H
H
Sugamura
K
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry*; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism*; D010450:Endopeptidases; D056827:Endosomal Sorting Complexes Required for Transport; D005434:Flow Cytometry; D018390:Gene Targeting; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D045726:Metalloproteases; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D043222:Ubiquitin Thiolesterase; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C486696:STAMBP protein, human; C491648:Stam protein, mouse; D010450:Endopeptidases; D045726:Metalloproteases; C441451:Stambp protein, mouse; D043222:Ubiquitin Thiolesterase