CC BY
27
OM&P
Section MOLECULAR NEUROSCIENCE
The cerebral cortex appears in stem amniotes and evolved in divergent manner in the two main amniote branches, namely the synapsids, that include premammals and mammals, and the sauropsids, now represented by reptiles and birds. Progress in our understanding of cortical neurogenesis, neuronal migration and layer formation allow to define common principles that are therefore presumably homologous and inherited from stem amniotes. On the other hand, critical features of mammalian cortex are absent in sauropsids and evolved after divergence of the two main radiations. Chief among those is the multilaminar organization of the mammalian cortex and its propensity to increase its surface by folding. Careful studies of human genetic disorders of cortical development and of animal models allow us to formulate mechanisms that can be tested using modern genetic and cellular technology. An integrated understanding of cortical development and evolution no longer seems an unattainable goal.
Cortical Expansion in the Development of Complex Mammalian Brains
Fumio Matsuzaki*
RIKEN Center for Developmental Biology, Japan. * Presenting e-mail: fumio@cdb.riken.jp
Introduction
Rapid expansion of brain size and complexity is a hallmark of mammalian evolution. The rodent dorsal brain, which is typically lissencephalic, forms a single primary germinal zone, the ventricular zone (VZ), which faces the ventricle on the apical side during development. In the VZ, self-renewing neural progenitors called radial glia undergo interkinetic nuclear movement and divide asymmetrically at the apical surface to give rise to a pair of daughter cells of distinct fates: another radial glial cell and an intermediate progenitor that divides once to generate a few neurons at the adjacent subventricular zone (SVZ). During the development of the complex brain, such as in ferret or primate, however, huge numbers of neurons are generated in the formation of the complex organization of the folded cortical structure. In such gyrencephalic brains, a new germinal zone, the outer SVZ (OSVZ), is formed during neurogenesis, and is thought to play important roles in the expansion of the neuronal population and fortmation of gyrencephaly.
Results and discussion
To gain a better understanding of the processes by which the OSVZ is formed from the VZ, we have used the ferret brain as a model of the complex brain in studies using long-term time-lapse imaging of brain slices, lineage analysis, and genetic perturbations (based on CRISPR/Cas9). We found that the cerebral cortex develops in a similar manner to the ganglionic eminence (the ventral side of the telencephalon) in ferret, unlike in rodent models. We discuss recent results from our group in light of this model of OSVZ formation.
References
1. Matsuzaki F, and Shitamukai A. Cell division modes and cleavage planes of neural progenitors during mammalian cortical development. Cold Spring Harb Perspect Biol. 2015; 7; a015719. doi: 10.1101/cshperspect.a015719 (2015).
2. Pilz GA, Shitamukai A, Reillo I, Pacary E, Schwausch J, Stahl R, Ninkovic J, Snippert HJ, Clevers H, Godinho L, Guillemot F, Borrell V, Matsuzaki F, Gote M. Amplification of progenitors in the mammalian telencephalon includes a new radial glial cell type. Nat Commun. 4:2125. doi: 10.1038/ncomms3125 (2013).
Distinct Epigenetic Functions of SOX2 in Self-Renewal and Differentiation
Flavio Cimadamore1, Alejandro Amador-Arjona1, Chun-Teng Huang1, Rusty Gage2, Alexey Terskikh1 *
1 Sanford Burnham Prebys Medical Discovery Institute, Neuroscience, La Jolla, CA;
2 Salk Institute, Laboratory of Genetics, La Jolla, CA. * Presenting e-mail: Terskikh@sbp.edu
Section MOLECULAR NEUROSCIENCE
Introduction
The HMG-box transcription factor SOX2 is ubiquitously expressed in multipotent neural stem-precursor cells (NPCs) and supports their self-renewal. SOX2 expression is also required for the onset of neurogenesis in the central and peripheral nervous systems. However, the exact SOX2 function and its molecular mechanism are poorly understood.
Methods/Results
We have uncovered two distinct epigenetic mechanism of Sox2 function in neural stem cell self-renewal and differentiation. Using human embryonic stem cell - derived NPC we found that Sox2 promotes proliferation of neural stem cells via LIN28/let7 pathway. Specifically, Sox2 promotes histone acetylation at Lin28 promoter thus maintaining Lin28 expression in NPCs, which is sufficient to maintain NPCs proliferation in the absence of Sox2 (1). Historically, SOX2 has been regarded as a transcription factor that opposes neurogenesis, and SOX2 repression must be relieved to allow initiation of transcription of the proneural gene NeuroDl. However, we found that SOX2 function is required to generate neurons both in central and peripheral nervous systems (2, 3). Mechanistically, we demonstrated that Sox2 primes epigenetic landscape inM NPCs enabling proper gene activation during the onset of neurogenesis. Namely, Sox2 binds to bivalently marked promoters of poised proneural genes where SOX2 functions to maintain the bivalent chromatin state by preventing excessive PRC2 activity (3).
Figure 1. Epigenetic Regulation of SOX2 at the Promoters of Poised Genes in Adult Hippocampal NPCs
Discussion
To our knowledge, this is the first example of a lineage-specific transcription factor that maintains the bivalent state at the promoters of poised genes, thus coordinating the onset of a developmental (neurogenic) program and consequently ensuring a robust and appropriate terminal (neuronal) differentiation process.
Conclusion
We propose that SOX2 sets a permissive epigenetic state in neural stem cells, thus enabling proper activation of the neuronal differentiation program under neurogenic cues.
References
1. Cimadamore et al., SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors. PNAS, 2013;110(32):
2. Cimadamore et al., Human ESC-Derived Neural Crest Model Reveals a Key Role for SOX2 in Sensory Neurogenesis. Cell stem cell, 2011;8(5):538-51.
3. Amador-Arjona et al., SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. PNAS, 2015;112(15).
* Active 7 chromatin
> Neurogenic factor
j Bivalent chromatin
