Signalling through the Type 1 Insulin-Like Growth Factor Receptor (IGF1R) Interacts with Canonical Wnt Signalling to Promote Neural Proliferation in Developing Brain

Autor: Qichen Hu, Seong Yong Lee, John R O'Kusky, Ping Ye
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: ASN Neuro, Vol 4 (2012)
Druh dokumentu: article
ISSN: 1759-0914
1759-9091
DOI: 10.1042/AN20120009
Popis: Signalling through the IGF1R [type 1 IGF (insulin-like growth factor) receptor] and canonical Wnt signalling are two signalling pathways that play critical roles in regulating neural cell generation and growth. To determine whether the signalling through the IGF1R can interact with the canonical Wnt signalling pathway in neural cells in vivo , we studied mutant mice with altered IGF signalling. We found that in mice with blunted IGF1R expression specifically in nestin-expressing neural cells (IGF1R Nestin–KO mice) the abundance of neural β-catenin was significantly reduced. Blunting IGF1R expression also markedly decreased: (i) the activity of a LacZ (β-galactosidase) reporter transgene that responds to Wnt nuclear signalling (LacZ TCF reporter transgene) and (ii) the number of proliferating neural precursors. In contrast, overexpressing IGF-I (insulin-like growth factor I) in brain markedly increased the activity of the LacZ TCF reporter transgene. Consistently, IGF-I treatment also markedly increased the activity of the LacZ TCF reporter transgene in embryonic neuron cultures that are derived from LacZ TCF Tg (transgenic) mice. Importantly, increasing the abundance of β-catenin in IGF1R Nestin–KO embryonic brains by suppressing the activity of GSK3β (glycogen synthase kinase-3β) significantly alleviated the phenotypic changes induced by IGF1R deficiency. These phenotypic changes includes: (i) retarded brain growth, (ii) reduced precursor proliferation and (iii) decreased neuronal number. Our current data, consistent with our previous study of cultured oligodendrocytes, strongly support the concept that IGF signalling interacts with canonical Wnt signalling in the developing brain to promote neural proliferation. The interaction of IGF and canonical Wnt signalling plays an important role in normal brain development by promoting neural precursor proliferation.
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