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

Author:

Lozano-Ureña Anna12,Lázaro-Carot Laura12,Jiménez-Villalba Esteban12,Montalbán-Loro Raquel12,Mateos-White Isabel12ORCID,Duart-Abadía Pere12,Martínez-Gurrea Irene12,Nakayama Keiichi I.3ORCID,Fariñas Isabel12,Kirstein Martina12ORCID,Gil-Sanz Cristina12ORCID,Ferrón Sacri R.12ORCID

Affiliation:

1. Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia 1 , Valencia 46100, Spain

2. Universidad de Valencia 2 Departamento de Biología Celular , , Valencia 46100, Spain

3. Medical Institute of Bioregulation, Kyushu University 3 Department of Molecular and Cellular Biology , , Fukuoka 819-0395, Japan

Abstract

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.

Funder

Ministerio de Ciencia e Innovación

Generalitat Valenciana

Universitat de València

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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