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Molecular and Cellular Biology, January 2009, p. 333-341, Vol. 29, No. 2
0270-7306/09/$08.00+0 doi:10.1128/MCB.00370-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Ott1 (Rbm15) Is Essential for Placental Vascular Branching Morphogenesis and Embryonic Development of the Heart and Spleen
Glen D. Raffel,1,
*
Gerald C. Chu,2,
Jonathan L. Jesneck,3,4
Dana E. Cullen,1
Roderick T. Bronson,5
Olivier A. Bernard,6,7 and
D. Gary Gilliland1,8*
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Departments of Medical Oncology,2 Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115,3 Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02141,4 Rodent Histopathology Core, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,5 INSERM E0210, Paris, France,6 Université René Descartes, Paris, France,7 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 021158
Received 4 March 2008/ Returned for modification 16 April 2008/ Accepted 23 October 2008
The infant leukemia-associated gene Ott1 (Rbm15) has broad regulatory effects within murine hematopoiesis. However, germ line Ott1 deletion results in fetal demise prior to embryonic day 10.5, indicating additional developmental requirements for Ott1. The spen gene family, to which Ott1 belongs, has a transcriptional activation/repression domain and RNA recognition motifs and has a significant role in the development of the head and thorax in Drosophila melanogaster. Early Ott1-deficient embryos show growth retardation and incomplete closure of the notochord. Further analysis demonstrated placental defects in the spongiotrophoblast and syncytiotrophoblast layers, resulting in an arrest of vascular branching morphogenesis. The rescue of the placental defect using a conditional allele with a trophoblast-sparing cre transgene allowed embryos to form a normal placenta and survive gestation. This outcome showed that the process of vascular branching morphogenesis in Ott1-deficient animals was regulated by the trophoblast compartment rather than the fetal vasculature. Mice surviving to term manifested hyposplenia and abnormal cardiac development. Analysis of global gene expression of Ott1-deficient embryonic hearts showed an enrichment of hypoxia-related genes and a significant alteration of several candidate genes critical for cardiac development. Thus, Ott1-dependent pathways, in addition to being implicated in leukemogenesis, may also be important for the pathogenesis of placental insufficiency and cardiac malformations.
* Corresponding author. Present address for Glen D. Raffel: Division of Hematology-Oncology, LRB306, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Phone: (508) 856-4887. Fax: (508) 856-6797. E-mail: glen.raffel{at}umassmed.edu. Mailing address for D. Gary Gilliland: Division of Hematology, Brigham and Women's Hospital, 1 Blackfan Cir., Boston, MA 02115. Phone: (617) 355-9092. Fax: (617) 355-9093. E-mail: ggilliland{at}rics.bwh.harvard.edu
Published ahead of print on 3 November 2008.
G.D.R. and G.C.C. contributed equally to this work.
Molecular and Cellular Biology, January 2009, p. 333-341, Vol. 29, No. 2
0270-7306/09/$08.00+0 doi:10.1128/MCB.00370-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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