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An Adenosine Triphosphatase of the Sucrose Nonfermenting 2 Family, Androgen Receptor-Interacting Protein 4, Is Essential for Mouse Embryonic Development and Cell Proliferation

Biomedicum Helsinki, Institute of Biomedicine, Physiology (F.-P.Z., A.D., J.J.P., O.A.J.) and Developmental Biology (H.S.), University of Helsinki, and Developmental Biology Program (J.P.), Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland; Department of Medical Biochemistry (J.J.P.), University of Kuopio, FI-70211 Kuopio, Finland; and Department of Clinical Chemistry (O.A.J.), Helsinki University Central Hospital, FI-00290 Helsinki, Finland

Address all correspondence and requests for reprints to: Olli A. Jänne, M.D., Ph.D., Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, FI-00014, Helsinki, Finland. E-mail: olli.janne{at}helsinki.fi.

An adenosine triphosphatase of the sucrose nonfermenting 2 protein family, androgen receptor-interacting protein 4 (ARIP4), modulates androgen receptor activity. To elucidate receptor-dependent and -independent functions of ARIP4, we have analyzed Arip4 gene-targeted mice. Heterozygous Arip4 mutants were normal. Arip4 is expressed mainly in the neural tube and limb buds during early embryonic development. Arip4^–/– embryos were abnormal already at embryonic d 9.5 (E9.5) and died by E11.5. At E9.5 and E10.5, almost all major tissues of Arip4-null embryos were proportionally smaller than those of wild-type embryos, and the neural tube was shrunk in some Arip4^–/– embryos. Dramatically reduced cell proliferation and increased apoptosis were observed in E9.5 and E10.5 Arip4-null embryos. Mouse embryonic fibroblasts (MEFs) isolated from Arip4^–/– embryos ceased to grow after two to three passages and exhibited increased apoptosis and decreased DNA synthesis compared with wild-type MEFs. Comparison of gene expression profiles of Arip4^–/– and wild-type MEFs at E9.5 revealed that putative ARIP4 target genes are involved in cell growth and proliferation, apoptosis, cell death, DNA replication and repair, and development. Collectively, ARIP4 plays an essential role in mouse embryonic development and cell proliferation, and it appears to coordinate multiple essential biological processes, possibly through a complex chromatin remodeling system.

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Coregulators:   ARIP4