Acceleration of mesoderm development and expansion of hematopoietic progenitors in differentiating ES cells by the mouse Mix-like homeodomain transcription factor.
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.
Willey
Stephen
S
Department of Medicine, Mt Sinai School of Medicine, New York, NY 10029-6574, USA.
Ayuso-Sacido
Angel
A
Zhang
Hailan
H
Fraser
Stuart T
ST
Sahr
Kenneth E
KE
Adlam
Matthew J
MJ
Kyba
Michael
M
Daley
George Q
GQ
Keller
Gordon
G
Baron
Margaret H
MH
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics; D005775:Gastrula / Q000166:cytology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D051379:Mice; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D000098908:Brachyury Protein
D005326:Fetal Proteins; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C464781:Mixl1 protein, mouse