Figure 7. Proposed model for Lfng-mediated regulation of NSC maintenance by progeny.
(A) In the resting state, Lfng-expressing NSC (green) is surrounded mostly by Delta1 (Dll)-expressing granule cells (GC, grey). Dll1 binds to the Lfng-modified Notch receptor on the NSC, which boosts Dll1-mediated Notch signaling by producing more NICDs and the NSC is kept quiescent but ready to undergo cell cycle if stimulated. Once activated, NSC (red) starts to produce ANPs. The first progeny (Type 2a, small dark yellow cells) do not express Notch ligands and the NSC continues to divide. As ANPs mature into late ANPs (Type 2b, yellow cells), they start to express Jag1. Jag1 binding to the Lfng-modified Notch receptor on the NSC does not generate NICD and thus the Notch signaling strength in the ‘mother’ NSC decreases. Eventually, the NSC is surrounded by mostly Jag1-expressing ANPs, and it exits active state (green NSC). Thus, in the resting state, the granule cell progeny prevents overt activation of NSCs, while in the active state, the ANP progeny prevents overt division of the NSC. These feedback signaling from the progeny both act to preserve the NSC population and the integrity of the niche. (B) The summary of the loss-of-function data, focusing on the number of activated NSCs (red) and the final outcomes of their division. Mice lacking Lfng and Dll1 have similar phenotypes: NSCs are recruited in bulk, they divide less and faster, and eventually lead to depletion of NSC population. In Lfng mutant mice, there is an increased transformation into astrocytes (blue). Mice lacking Jag1 have the opposite phenotype: while NSCs are activated as in the wild-type, they divide more and longer, and produce large clusters of ANPs as well as self-renew.