Editors' ChoiceStem Cells

EGFL7: An Anti-Notch Ligand

Science Signaling  14 Jul 2009:
Vol. 2, Issue 79, pp. ec236
DOI: 10.1126/scisignal.279ec236

Epidermal growth factor–like domain 7 (EGFL7) is a secreted protein that has been implicated in cell migration and blood vessel formation. The receptor that EGFL7 binds is unknown. The Notch pathway is involved in both angiogenesis and neural development. Notch is a transmembrane receptor that is cleaved to release the transcriptional regulator NICD (the Notch intracellular domain) in response to ligands, such as Jagged. Schmidt et al. showed by yeast two-hybrid experiments and coimmunoprecipitation and binding assays that EGFL7 and the extracellular domain of Notch interacted and that the interaction could be mediated by either the Emilin-like domain (EMI) or the EGF-like domains of EGFL7 and required the EGF-like repeats on Notch. When Jagged and Notch were coexpressed with increasing amounts of EGFL7, the interaction between Jagged and Notch was disrupted. EGFL7 decreased Notch signaling in response to Jagged. In a more physiological setting, the effect of EGFL7 on cultured murine neural stem cell (NSC) proliferation, self-renewal, and differentiation in response to Notch signaling was assayed. Overexpression of EGFL7 or addition of recombinant EGFL7 decreased, and EGFL7 knockdown decreased, NSC proliferation and self-renewal. The effects of EGFL7 on the NSCs appeared to be due to inhibition of Notch signaling, as forced expression of EGFL7 also decreased the expression of the Notch target gene Hes and the decrease in self-renewal was overcome by NICD. When NSCs were plated on EGFL7-coated coverslips, differentiation into neurons and oligodendrocytes was increased and differentiation into astrocytes, which is Notch dependent, was decreased. Transcripts for EGFL7 were most abundant in the cortex and were less abundant in the subventricular zone, where NSCs reside in the adult brain, and in cultured neurospheres. The authors suggest that by competing with Jagged in the brain, EGFL7 may trigger differentiation of NSCs that have been mobilized from the subventricular zone.

M. H. H. Schmidt, F. Bicker, I. Nikolic, J. Meister, T. Babuke, S. Picuric, W. Müller-Esterl, K. H. Plate, I. Dikic, Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nat. Cell Biol. 11, 873–880 (2009). [PubMed]