IGF2 interacts with the imprinted gene Cdkn1c to promote terminal differentiation of neural stem cells

Abstract

Adult neurogenesis is supported by multipotent neural stem cells (NSCs) with unique properties and growth requirements. Adult NSCs constitute a reversibly quiescent cell population that can be activated by extracellular signals from the microenvironment in which they reside in vivo. Although genomic imprinting plays a role in adult neurogenesis through dose regulation of some relevant signals, the roles of many imprinted genes in the process remain elusive. Insulin-like growth factor 2 (IGF2) is encoded by an imprinted gene that contributes to NSC maintenance in the adult subventricular zone through a biallelic expression in only the vascular compartment. We show here that IGF2 additionally promotes terminal differentiation of NSCs into astrocytes, neurons and oligodendrocytes by inducing the expression of the maternally expressed gene cyclin-dependent kinase inhibitor 1c (Cdkn1c), encoding the cell cycle inhibitor p57. Using intraventricular infusion of recombinant IGF2 in a conditional mutant strain with Cdkn1c-deficient NSCs, we confirm that p57 partially mediates the differentiation effects of IGF2 in NSCs and that this occurs independently of its role in cell-cycle progression, balancing the relationship between astrogliogenesis, neurogenesis and oligodendrogenesis.

Identification ofPappaandSall3as Gli3 direct target genes acting downstream of cilia signalling in corticogenesis

“…Interestingly, Igf signalling can promote neuronal differentiation under certain conditions. Nestin / Igf1 transgenic mice showed a preferential increase in the formation of layer V neurons (Hodge et al, 2005) and Igf2 also promoted adult neural stem cell differentiation through upregulation of Cdkn1c (Lozano-Urena et al, 2023) which is augmented in Inpp5e mutants but decreased in E11.5 Gli3 conditional mutants (Supp. Table 1).…”

Calcium Folate Nanoparticles as Dual‐Functional Neural Inducing Factors to Promote the Differentiation of Neural Stem Cells into Cholinergic Neurons

“…Specifically, Igf2 is positively correlated with the differentiation of NSCs into neurons and is related to PI3K‐Akt signaling pathway. [ 26 ] Igf2 can increase the protein levels of the ChAT in AD mice. [ 27 ] Gdnf and Ngf are important for survival and function of cholinergic neurons.…”

Epigenetic regulation in adult neural stem cells

“…It is possible that dosage-sensitive transcriptional regulation of Igf2 through its imprinted expression may be crucial for adult neurogenesis. Interestingly, IGF2 is also important for terminal differentiation of NSCs into neurons, astrocytes and oligodendrocytes through regulation of another imprinted gene Cdkn1c encoding a cell-cycle inhibitor p57 ( Lozano-Urena et al, 2023 ). Thus, DNA methylation plays diverse and important roles in the maintenance, proliferation and differentiation of NSCs.…”