| Project/Area Number |
16310141
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied genomics
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| Research Institution | Kazusa DNA Research Institute |
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Principal Investigator |
NAKAYAMA Manabu Kazusa DNA Research Institute, Department of Human Gene Research, Chief Research Scientist, ヒト遺伝子研究部, 主任研究員 (30370927)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2005: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2004: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | comprehensive analysis / functional genomics / large protein / KIAA / KO mice / human genome project / brain specific expression / early development |
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| Research Abstract |
To prioritize their functional analysis among thousands of genes in the typical mammalian genome and to decrease the likelihood of producing gene-targeted mice that lack overt phenotypes, we propose that initial analysis focus on genes encoding large proteins. At least some large proteins are likely to serve as frameworks for the intricate assembly of protein complexes ; thus, inactivation of their genes is likely to render definitive, observable phenotypes. Here, we describe the functional characterization of the murine homologues of five human KIAA genes (KIAA1409, KIAA1440, KIAA1447, KIAA1768, KIAA1276) that encode large proteins. Gene-targeted mice showed phenotypic and developmental defects resulting from the functional deletion of three of these five genes. Mice with targeted disruption of KIAA1409 lacked the ability to drink milk and those with targeted disruption of KIAA1447 displayed hind leg motor dysfunction. Disruption of KIAA1440 led to embryonic lethality at the blastocyst stage. The high success rate of our approach demonstrates the rationale for the genome-wide functional examination of large proteins in mice using reverse genetics. Moreover, our approach brings a new perspective to the world of biology : a protein complex can be thought of as being organized hierarchically in terms of function. Some proteins are essential for the proper functioning of and integrity of the complex ; others are relatively less important, taking on modifier roles. We propose that extremely large proteins are the key element of a protein complex because they function as the framework around which the complex is assembled.
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