title: Defects of the heart, eye, and megakaryocytes in peroxisome proliferator activator receptor-binding protein (PBP) null embryos implicate GATA family of transcription factors.
abstract: Peroxisome proliferator activator receptor (PPAR)-binding protein (PBP) is an important coactivator for PPARgamma and other nuclear receptors. It has been identified as an integral component of a multiprotein thyroid hormone receptor-associated protein/vitamin D(3) receptor-interacting protein/activator-recruited cofactor complexes required for transcriptional activity. Here, we show that PBP is critical for the development of placenta and for the normal embryonic development of the heart, eye, vascular, and hematopoietic systems. The primary functional cause of embryonic lethality at embryonic day11.5 observed with PBP null mutation was cardiac failure because of noncompaction of the ventricular myocardium and resultant ventricular dilatation. There was a paucity of retinal pigment, defective lens formation, excessive systemic angiogenesis, a deficiency in the number of megakaryocytes, and an arrest in erythrocytic differentiation. Some of these defects involve PPARgamma and retinoid-sensitive sites, whereas others have not been recognized in the PPAR-signaling pathway. Phenotypic changes in four organ systems observed in PBP null mice overlapped with those in mice deficient in members of GATA, a family of transcription factors known to regulate differentiation of megakaryocytes, erythrocytes, and adipocytes. We demonstrate that PBP interacts with all five GATA factors analyzed, GATA-1, GATA-2, GATA-3, GATA-4, and GATA-6, and show that the binding of GATA-1, GATA-4, and GATA-6 to PBP is not dependent on the nuclear receptor recognition sequence motif LXXLL (where L is leucine and X is any amino acid) in PBP. Coexpression of PBP with GATA-3 markedly enhanced transcriptional activity of GATA-3 in nonhematopoietic cells. These observations identify the GATA family of transcription factors as a new interacting partner of PBP and demonstrate that PBP is essential for normal development of vital organ systems.
authors.affiliation: Department of Pathology, Northwestern University School of Medicine, Chicago, Illinois 60611-3008, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Chao
authors.initials: C
authors.lastname: Qi
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
authors.forename: Veronica
authors.initials: V
authors.lastname: Stellmach
authors.forename: M Sambasiva
authors.initials: MS
authors.lastname: Rao
authors.forename: James D
authors.initials: JD
authors.lastname: Engel
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism; D005314:Embryonic and Fetal Development; D004912:Erythrocytes / Q000166:cytology; D050981:Erythroid-Specific DNA-Binding Factors; D005124:Eye Abnormalities / Q000235:genetics*; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000235:genetics*; D056913:Mediator Complex Subunit 1; D008533:Megakaryocytes / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse; C494748:Gata3 protein, mouse; C494760:Gata6 protein, mouse; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D015534:Trans-Activators; D014157:Transcription Factors