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Molecular and Cellular Biology, December 2003, p. 8486-8494, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8486-8494.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Hematopoietic Development in the Aorta-Gonad-Mesonephros Region Mediated by Lnk Adaptor Protein

Ikuo Nobuhisa,1 Makiko Takizawa,1 Satoshi Takaki,2 Hirofumi Inoue,1 Keisuke Okita,1 Masaya Ueno,1,{dagger} Kiyoshi Takatsu,2 and Tetsuya Taga1*

Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto,1 Division of Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan2

Received 11 April 2003/ Returned for modification 27 May 2003/ Accepted 15 August 2003

Development of hematopoietic cells in the aorta-gonad-mesonephros (AGM) region in the midgestation mouse embryo involves a multistep process, sequentially changing from endothelial cell-like cells, including hemangioblasts, into hematopoietic stem cells, progenitors, and/or lineage-committed cells. An adaptor molecule, Lnk, is known to negatively control the production of pro- and pre-B cells and hematopoietic progenitor cells in adult bone marrow. Here we show a role of Lnk in hematopoietic development in the AGM region. Lnk was predominantly expressed in the endothelial cells lining the dorsal aorta at embryonic day 11.5 (E11.5). Overexpression of Lnk in the primary culture of the AGM region at E11.5 suppressed the emergence of CD45+ hematopoietic cells. Point mutation in the SH2 domain of Lnk, which abolishes the binding capability of Lnk to c-Kit upon stimulation with stem cell factor (SCF), led to loss of Lnk-dependent inhibition of hematopoietic cell development in AGM cultures, suggesting Lnk-mediated inhibition of the SCF/c-Kit signaling pathway. In cultured AGM cells from Lnk homozygous mutant mouse embryos, the number of emerged CD45+ cells was 2.5-fold larger than that from heterozygous littermates. Furthermore, aorta cells of E11.5 Lnk homozygous mutant mice also showed enhanced hematopoietic colony-forming activity. Thus, Lnk is a negative regulator of hematopoiesis in the AGM region.

* Corresponding author. Mailing address: Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1, Honjo, Kumamoto 860-0811, Japan. Phone and fax: 81-96-373-6610. E-mail: taga{at}kaiju.medic.kumamoto-u.ac.jp.

{dagger} Present address: Department of Stem Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Molecular and Cellular Biology, December 2003, p. 8486-8494, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8486-8494.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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