Endothelial-to-hematopoietic transition is induced by Notch glycosylation and upregulation of Mycn

Abstract

A better understanding of the molecular mechanisms driving hematopoietic stem cell (HSC) specification and expansion may enable better pharmacological strategies to produce them in sufficient numbers for transplantation. In the embryo, HSCs arise from a defined subset of arterial endothelial cells (ECs) located in the aorta-gonad-mesonephros (AGM) region that undergo endothelial to hematopoietic transition (EHT). Arterialization and HSC development are generally believed to require the action of Notch. Here we show that although Notch activity is initially required for arterialization,it is detrimental to subsequent EHT. Mechanistically, we show that effective EHT depends on a Mfng induced decrease in Jag1-Notch signaling in hemogenic ECs. This causes upregulation of Mycn, an important metabolic and cell-cycle regulator that we found to be required for EHT. During the subsequent development of hematopoietic lineages, Mycn expression decreases and its function is taken on by the homologous Myc gene.

Radical fringe facilitates NOTCH1 and JAG1cisinteractions to sustain Hematopoietic stem cell fate

“…Therefore, it is concluded that Notch activity is compulsory for HSC emergence and arterial formation, but the timing and the threshold of Notch activity as well as the precise interactions of receptors and ligands remained undetermined. In the AGM, blocking DLL4 or inhibiting Notch activity with -secretase inhibitors can increase HSPC activity 62-64 , yet absence of JAG1 leads to a dramatic loss of IAHC 65,66 . Importantly, the phenotypes of blocking DLL4 with an antibody or treatment with -secretase inhibitors is dependent on the developmental stage of HE and HSPC; blocking DLL4 ex vivo most efficiently increases HSC activity when applied at early AGM stages (31-34s) 62 .…”

“…19.537430 doi: bioRxiv preprint Notch activity tracing transgenic mouse models defined lower Notch activity in IAHC compared to their arterial surrounding 45 and blocking DLL4 with a specific antibody at the time of HSC emergence increases HSC frequency 46 . However, both complete and endothelial specific KO of the notch ligand Jag1 shows a specific loss of IAHC and HSC activity, although the artery formation is intact 47,48 . Finally, maturing T2-HSCs are Notch independent 49 .…”

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

“…Unlike the B cell, myeloid and erythroid lineages, T cells develop in the thymus, passing through the liver only briefly (~E12.0 in mouse) as NOTCH1 activation specifies the T from B cell lineages from the common progenitor [21,22,26]. To assess the hematopoietic progenitor populations developmentally regulated by Notch signaling [23][24][25]110], we used flow cytometry and analyzed the first waves of definitive immune cell production prior to the emergence of the liver (Fig. S10A, B).…”

“…ALGS is characterized by bile duct paucity (often resulting in liver transplantation), developmental heart defects, butterfly vertebrae, characteristic facies, posterior embryotoxon and multiple associated symptoms, including the immune dysregulation, present with different penetrance [8,14,15] . Notch signaling controls development of both liver epithelial cells (hepatocytes and cholangiocytes) [16][17][18][19][20] and the immune cells [21][22][23][24][25][26] yet how the immune system is affected in ALGS, and its impact on liver disease progression, has not yet been comprehensively addressed.…”