An Allelic Series Uncovers Novel Roles of the BRCT Domain-Containing Protein PTIP in Mouse Embryonic Vascular Development

Abstract

Pax transactivation domain-interacting protein (PTIP, or PAXIP1) is required for mouse development and has been implicated in DNA damage responses and histone modification. However, the physiological roles of PTIP during embryogenesis remain unclear due to early embryonic lethality of null mutants. We describe two N-ethyl N-nitrosourea-induced hypomorphic missense alleles of Ptip, each of which alters one of the six encoded BRCT domains. Phenotypic characterization of these mutants revealed important functions of PTIP in vasculogenesis and chorioplacental development that appear unrelated to activities in DNA repair or global histone modification. The results of gene expression profiling and in vitro angiogenesis assays indicated that PTIP modulates a transcriptional program, centered around Vegfa, that drives the migration of endothelial cells to properly form the embryonic vasculature. These and other data suggest that PTIP has multiple functions, one of which is to promote the formation of transcriptional complexes that provide specificity of developmental gene expression.

ACKNOWLEDGMENTS

We thank Gregory Dressler for providing us with Ptip knockout mice and anti-mouse PTIP antibody, Xu Peng for helpful discussions, Robert Munroe and Ian Welsh for technical help, and T. O'Brien for advice on the manuscript.

This work was supported by NIH grant R01 HD35984 to J.C.S.