Cyclin-Dependent Kinase 4 Regulates Adult Neural Stem Cell Proliferation and Differentiation in Response to Insulin

Abstract

Insulin is one of the standard components used to culture primary neurospheres. Although it stimulates growth of different types of cells, the effects of insulin on adult neural stem cells (NSCs) have not been well characterized. Here, we reveal that insulin stimulates proliferation, but not survival or self-renewal, of adult NSCs. This effect is mediated by insulin receptor substrate 2 (IRS2) and subsequent activation of the protein kinase B (or Akt), leading to increased activity of the G1-phase cyclin-dependent kinase 4 (Cdk4) and cell cycle progression. Neurospheres isolated from Irs2-deficient mice are reduced in size and fail to expand in culture and this impaired proliferation is rescued by introduction of a constitutively active Cdk4 (Cdk4 ). More interestingly, activation of the IRS2/Akt/Cdk4 signaling pathway by insulin is also necessary for the generation in vitro of neurons and oligodendrocytes from NSCs. Furthermore, the IRS2/Cdk4 pathway is also required for neuritogenesis, an aspect of neuronal maturation that has not been previously linked to regulation of the cell cycle. Differentiation of NSCs usually follows exit from the cell cycle due to increased levels of CDK-inhibitors which prevent activation of CDKs. In contrast, our data indicate that IRS2-mediated Cdk4 activity in response to a mitogen such as insulin promotes terminal differentiation of adult NSCs. Stem Cells 2017;35:2403-2416.

The Insulin Receptor Adaptor IRS2 is an APC/C Substrate That Promotes Cell Cycle Protein Expression and a Robust Spindle Assembly Checkpoint

“…In IRS2-deficient mice with consequent type 2 diabetes, some have attributed the reduced b cell mass to a failure of b cells to re-enter the cell cycle following division (63). Our findings that APC/C Cdh1 inhibition stabilizes IRS2 and that IRS2 promotes the expression of cell cycle regulatory proteins, coupled with data from others showing that IRS2 can stimulate cell cycle entry (61), suggest that APC/C Cdh1 inhibition may represent a possible approach for stimulating proliferation in quiescent b cells via the stabilization of IRS2.…”

Divide or Commit – Revisiting the Role of Cell Cycle Regulators in Adult Hippocampal Neurogenesis

“…Rather, they provided persuasive evidence for a link between G 1 length and differentiation of NSC (Lange and Calegari, 2010; Salomoni and Calegari, 2010). More direct evidence was presented by subsequent in vitro studies (Roccio et al, 2013; Chirivella et al, 2017). Inhibition of CDK4 in precursors isolated from the adult SGZ or SVZ proportionally increased the number of cells in G 1 and forced neuronal differentiation.…”

E2F1, a Novel Regulator of Metabolism

“…Many studies have focused on the mitogenic signals that drive E2F1 activation in cancer cells, but how E2F1 is activated in other pathological conditions such as obesity is just beginning to be understood. The CDK4-pRB-E2F1 pathway can be stimulated both by glucose and by insulin in different tissues involved in global metabolic homeostasis ( 16 , 24 , 29 , 95 , 98 ). One possibility is that during obesity, hyperglycemia and/or hyperinsulinemia render pRB hyperphosphorylated ( 50 , 61 , 65 ).…”