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Delineation of the Regulatory Networks Controlling Neural Stem Cell Function

Review of “Sox2 controls neural stem cell self‐renewal through a Fos‐centered gene regulatory network” from STEM CELLS by Stuart P. Atkinson

To decipher the molecular mechanisms that sustain the self-renewal and proliferation of postnatal neural stem cells (NSCs), researchers led by Silvia K. Nicolis (University of Milano‐Bicocca, Milan, Italy) sought to identify those factors that could sustain in-vitro stem cell function following the deletion of the all-important SOX2 (Sex-determining region Y-box 2) transcription factor [1, 2]. Of note, a previous related study described how the re‐expression of Socs3 (Suppressor of cytokine signaling 3 - highly downregulated as a consequence of Sox2 deletion) rescued the long‐term self‐renewal of NSCs [3]. In a recent STEM CELLS article, Pagin et al. report on their exploration of additional factors that sustain Sox2-deficient NSCs in the hope of delineating downstream regulatory networks [4] and identifying targets for pharmacological manipulation to support reparative/regenerative therapies in the postnatal brain.

The authors began their research by evaluating the forced expression of genes whose expression suffered severe downregulation following Sox2 loss in mouse NSCs. Initial studies found that the transduction of Fos (Fos proto-oncogene, AP-1 transcription factor subunit), which encodes a transcription factor that forms a dimer with Jun (Jun proto-oncogene, AP-1 transcription factor subunit), prompted the increased expression of Socs3 and the efficient rescue of long-term proliferation and self-renewal in Sox2-deficient NSCs. Furthermore, in confirmation of the importance of FOS, the pharmacological inhibition of DNA binding and hence the transcriptional activity of FOS in wild-type NSCs prompted a reduction in proliferation/self-renewal and Socs3 expression; meanwhile, the CRISPR/Cas9‐mediated induction of mutations in the Fos gene correlated with a decrease in the long-term self-renewing capacity of wild-type NSCs.

With this knowledge in hand, the authors next mined data from previous SOX2 chromatin immunoprecipitation (ChIP)-sequencing and RNA polymerase II chromatin interaction analysis by paired-end tag sequencing (ChIA-PET – used to detect long‐range promoter‐enhancer chromatin interactions) analyses in NSCs [3] and highlighted SOX2 interactions with the regulatory regions of the genes encoding FOS, JUN, and the SOCS3 regulator EGR2 (early growth response 2). In confirmation, the re-expression of Sox2 in Sox2-deficient NSCs led to the progressive induction of Fos and Socs3 gene expression. Finally, the study also established that SOX2, JUN, and FOS all bound the Socs3 promoter in wild-type NSCs, suggesting direct transcriptional regulation.

Overall, these detailed analyses delineate a SOX2‐dependent FOS/JUN/EGR‐SOCS3 network that significantly contributes to the in-vitro proliferation and long-term maintenance of mouse NSCs, which opens a new avenue of exploration to identify additional factors that regulate NSC function.

For more on the regulatory networks that control the self-renewal and proliferation of NSCs, stay tuned to the Stem Cells Portal!

References

  1. Favaro R, Valotta M, Ferri ALM, et al., Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nature Neuroscience 2009;12:1248-1256.
  2. Pevny LH and Nicolis SK, Sox2 roles in neural stem cells. The International Journal of Biochemistry & Cell Biology 2010;42:421-424.
  3. Bertolini JA, Favaro R, Zhu Y, et al., Mapping the Global Chromatin Connectivity Network for Sox2 Function in Neural Stem Cell Maintenance. Cell Stem Cell 2019;24:462-476.e6.
  4. Pagin M, Pernebrink M, Giubbolini S, et al., Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network. STEM CELLS 2021;39:1107-1119.