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¹ The Department of Comparative Medicine, University of Washington, Seattle, WA 98195
² Celltech R & D, Inc., Bothell, WA 98021
³ Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
⁴ The McLaughlin Research Institute, Great Falls, MT 59405
⁵ Amnis, Inc., Seattle, WA 98121

CORRESPONDENCE Brian M. Iritani: biritani{at}u.washington.edu

Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4^–CD8^– (double negative) to CD4⁺CD8⁺ (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor B (NF-B)–dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-B–dependent transcription proceeds independently of Hem1 and F-actin polymerization.

M.W. Appleby and F. Ramsdell's present address is ZymoGenetics, Inc., Seattle, WA 98102.

K. Staehling-Hampton's present address is Stowers Institute for Medical Research, Kansas City, MO 64110.

Y. Zhang's present address is Amgen Inc, San Francisco, CA 94080.

© 2008 Park et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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