Figure 1.

Tumour suppressor pathways implicated in the age-associated neurogenic decline of the mouse SVZ. (A) In SVZ NSPCs, the let7b microRNA represses translation of the Hmga2 protein, which act as a transcriptional repressor for the gene encoding for the JunB transcription factor. In turn, JunB promotes expression of the Cdk inhibitor p16^Ink4a. During aging (grey triangles), let7b levels increase, leading to enhanced activity of p16^Ink4a and to a decrease in neurogenesis. (B) In SVZ NSPCs, the Wip1 phosphatase acts as an inhibitor of p53, whose transcriptional activity promotes p21^Cip1 expression. In turn, p21^Cip1 can hinder neurogenesis through several mechanisms: by directly inhibiting NSPC proliferation due to its Cdk inhibitory activity, or by acting as a transcription factor to promote expression of the anti-neurogenic factors Bmp2 and Dkk3. During aging, Wip1 levels decrease, leading to enhanced p21^Cip1 activity and a reduction of neurogenesis. The question mark indicates that the regulation of Dkk3 expression by the p53 pathway may occur independently of p21^Cip1. Age-related changes in Bmp2 levels in the SVZ have not been described yet. See text for further details.