Title:
Epigenetic regulation of neural stem cell fate specification and its application to regenerative medicine

Kinichi Nakashima
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology

Abstract:
It has become apparent that epigenetic mechanisms play critical roles in fate determination of neural stem cells (NSCs). In this presentation, I will introduce you our two recent studies regarding DNA methylation and histone acetylation in the regulation of NSC fate specification.

<Part I>
During mid-gestation, NSCs differentiate only into neurons. Generation of astrocytes is prevented at this stage, because astrocyte-specific gene promoters are methylated. I here show that Notch ligands are expressed on committed neuronal precursors and young neurons in mid-gestational telencephalon, and that neighboring Notch-activated NSCs acquire the potential to become astrocytes. Activation of the Notch signaling pathway in mid-gestational NSCs induces expression of the transcription factor nuclear factor-I,
which binds to astrocytic gene promoters, resulting in demethylation of astrocyte-specific genes. These findings provide a mechanistic explanation for why neurons come first: committed neuronal precursors and young neurons potentiate remaining NSCs to differentiate into the next cell lineage, astrocytes.

<Part II>
The body’s capacity to restore damaged neural networks in the injured CNS is severely limited. Here, using a mouse model of spinal cord injury (SCI), I show that combined transplantation of NSCs and administration of valproic acid (VPA), a known antiepileptic and histone deacetylase inhibitor, synergistically enhances hindlimb functional restoration. Preferential differentiation of transplanted NSCs into neurons was promoted in VPA-treated mice . Anterograde corticospinal tract tracing revealed that transplant-derived neurons reconstructed broken neuronal circuits , thereby allowing them to transmit signals in a relay manner . Ablation of the transplanted cells abolished the recovery of hindlimb motor function, confirming that they contributed directly to restored motor function. These findings raise the possibility that epigenetic status in transplanted NSCs can be manipulated to provide effective treatment for SCI.

References：
１． Namihira M., Kohyama J., Semi K., Sanosaka T., Deneen B., Taga T., Nakashima K. Committed Neuronal Precursors Confer Astrocytic Potential on Residual Neural Precursor Cells. Dev. Cell 16, 245-255 (2009).
２． Namihira M., Kohyama J., Abematsu M., Nakashima K. Epigenetic mechanisms regulating fate specification of neural stem cells. Philos Trans R Soc Lond B Biol Sci 363, 2099-109 (2008).