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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3122-3130.
Prepublished online as a Blood First Edition Paper on January 10, 2006; DOI 10.1182/blood-2005-10-4120.
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HEMATOPOIESIS
Acceleration of mesoderm development and expansion of hematopoietic progenitors in differentiating ES cells by the mouse Mix-like homeodomain transcription factor
Stephen Willey,
Angel Ayuso-Sacido,
Hailan Zhang,
Stuart T. Fraser,
Kenneth E. Sahr,
Matthew J. Adlam,
Michael Kyba,
George Q. Daley,
Gordon Keller, and
Margaret H. Baron
From the Departments of Medicine, Gene and Cell Medicine, and Oncological Sciences and Molecular, Cellular and Developmental Biology, Mount Sinai School of Medicine, New York, NY; Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas; and Division of Hematology/Oncology, Children's Hospital, Boston, MA.
The cellular and molecular events underlying the formation and differentiation of mesoderm to derivatives such as blood are critical to our understanding of the development and function of many tissues and organ systems. How different mesodermal populations are set aside to form specific lineages is not well understood. Although previous genetic studies in the mouse embryo have pointed to a critical role for the homeobox gene Mix-like (mMix) in gastrulation, its function in mesoderm development remains unclear. Hematopoietic defects have been identified in differentiating embryonic stem cells in which mMix was genetically inactivated. Here we show that conditional induction of mMix in embryonic stem cell–derived embryoid bodies results in the early activation of mesodermal markers prior to expression of Brachyury/T and acceleration of the mesodermal developmental program. Strikingly, increased numbers of mesodermal, hemangioblastic, and hematopoietic progenitors form in response to premature activation of mMix. Differentiation to primitive (embryonic) and definitive (adult type) blood cells proceeds normally and without an apparent bias in the representation of different hematopoietic cell fates. Therefore, the mouse Mix gene functions early in the recruitment and/or expansion of mesodermal progenitors to the hemangioblastic and hematopoietic lineages.
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