You are here

| Neural Stem Cells

Exploring how Insulin Affects Neural Stem Cells: An New role for Cdk4!



Review of “Cyclin-Dependent Kinase 4 Regulates Adult Neural Stem Cell Proliferation and Differentiation in Response to Insulin” from STEM CELLS by Stuart P. Atkinson

The replacement of neuronal cells lost due to damage or disease requires a fundamental appreciation of the processes that control neural stem cell (NSC) proliferation, differentiation, and maturation to create functionally mature cells. A new study from the laboratories of Isabel Fariñas (Universidad de Valencia) and Deborah Burks (Centro de Investigación Príncipe Felipe, Valencia, Spain) hopes to bring us one step further towards this lofty goal in a new STEM CELLS study [1].  

Chirivella et al. report how insulin, a standard growth media factor, promotes the proliferation and differentiation of adult NSCs derived from the ventricular-subventricular zone (V-SVZ) of the mouse brain [2, 3]. Could these exciting new findings boost regenerative strategies for neurodegenerative diseases?

To answer that question, let’s dive into the study’s findings:

  • Insulin and Insulin-like growth factor (IGF) I/II treatment enhanced the proliferation of V-SVZ NSCs growing in neurospheres via the activation of insulin receptor substrate 2 (IRS2) signaling
    • IRS2 activates protein kinase B (Akt), which subsequently enables G1-phase cyclin-dependent kinase 4 (Cdk4) activity and, subsequently, cell cycle progression
    • However, Insulin did not influence NSC survival or self-renewal 
  • Insulin also stimulated differentiation and neuritogenesis through the IRS2/Akt/Cdk4 pathway
    • The in vitro generation of neurons and oligodendrocytes from NSCs requires IRS2-mediated signaling
    • The sprouting of neurites (which become axons and dendrites) represents a pivotal event in early neuronal differentiation and maturation

While many studies have reported that exit from the cell cycle caused by Cdk-inhibitors leads to NSC differentiation, this exciting new report instead links IRS2-mediated Cdk4 activity to terminal differentiation of adult NSCs. Findings such as these will be critical for efficient in vitro neuron production or progenitor maturation and their application as a treatment strategy for neurodegenerative diseases. To this end, the authors note that the next step will be to identify further molecular mechanisms targeted by Cdk4 activity in NSCs.

To keep abreast of all the new findings on NSCs in vivo and in vitro, stay tuned to the Stem Cells Portal.


  1. Chirivella, L., et al., Cyclin-Dependent Kinase 4 Regulates Adult Neural Stem Cell Proliferation and Differentiation in Response to Insulin. STEM CELLS 2017;35:2403-2416.
  2. Reynolds, B. and S. Weiss, Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707-1710.
  3. Belenguer, G., et al., Isolation, culture and analysis of adult subependymal neural stem cells. Differentiation 2016;91:28-41.