The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells.

Genes Dev 2014 Mar;28(6):576-93

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

Notch1 is required to generate the earliest embryonic hematopoietic stem cells (HSCs); however since Notch-deficient embryos die early in gestation, additional functions for Notch in embryonic HSC biology have not been described. We used two complementary genetic models to address this important biological question. Unlike Notch1-deficient mice, mice lacking the conserved Notch1 transcriptional activation domain (TAD) show attenuated Notch1 function in vivo and survive until late gestation, succumbing to multiple cardiac abnormalities. Notch1 TAD-deficient HSCs emerge and successfully migrate to the fetal liver but are decreased in frequency by embryonic day 14.5. In addition, TAD-deficient fetal liver HSCs fail to compete with wild-type HSCs in bone marrow transplant experiments. This phenotype is independently recapitulated by conditional knockout of Rbpj, a core Notch pathway component. In vitro analysis of Notch1 TAD-deficient cells shows that the Notch1 TAD is important to properly assemble the Notch1/Rbpj/Maml trimolecular transcription complex. Together, these studies reveal an essential role for the Notch1 TAD in fetal development and identify important cell-autonomous functions for Notch1 signaling in fetal HSC homeostasis.

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.227496.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967047PMC
March 2014
44 Reads

Publication Analysis

Top Keywords

notch1
10
hematopoietic stem
8
fetal liver
8
notch1 signaling
8
stem cells
8
cells notch1
8
notch1 tad
8
notch1 tad-deficient
8
role notch1
8
signaling fetal
8
activation domain
8
notch1 transcriptional
8
transcriptional activation
8
fetal
5
tad properly
4
transcription complex
4
succumbing multiple
4
gestation succumbing
4
multiple cardiac
4
abnormalities notch1
4

Similar Publications