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Section MOLECULAR NEUROSCIENCE
genomic, and cell biological tools including mouse genetics and live imaging. One major research direction focuses on post-transcriptional RNA regulation in neural progenitor behavior and function. A second research focus is aimed at understanding how human-specific enhancers contribute to unique features of human brain development, including progenitor proliferation. This seminar will discuss new discoveries from our lab including how mitosis impacts progenitor cell fate specification in the developing brain, and layers of dynamic RNA regulation in neural progenitors.
Becoming a New Neuron in the Cerebral Cortex
Denis Jabaudon*
Dpt. of Basic Neuroscience, University of Geneva, Switeerland. * Presenting e-mail: denis.jabaudon@unige.ch
During neocortical development, excitatory neurons are born in the ventricular zone and migrate to the cortex, where they form the circuits that underlie mammalian skilled processing abilities. While the genetic programs that specify distinct subtypes of neurons within the neocortex are increasingly understood, how neuronal identity is dynamically acquired upon progenitor division is largely unknown. Identifying these primordial transcriptional processes is critical to understand how progenitor behavior is coupled to neuronal fate, and to provide mechanical insights into postmitotic neuron plasticity. Here, we will discuss recent findings from our laboratory on the mitotic and early-postmitotic biology of progenitors and their daughter cells, and how they inform neuronal specification and circuit assembly in the developing neocortex.
Dynamic Control of Neural Stem Cells
Ryoichiro Kageyama*
Institute for Virus Research; WPI-iCeMS, Kyoto University, Kyoto 606-8507, Japan. * Presenting e-mail: rkageyam@virus.kyoto-u.ac.jp
During brain development, neural stem cells gradually change their competency, giving rise to various types of neurons first and glial cells later. It is thus very important to maintain neural stem cells until the final stage of development to generate a full diversity of cell types. The basic helix-loop-helix (bHLH) factor Hesl plays an important role in maintenance of neural stem cells by repressing proneural gene expression. We found that the Hes1 expression oscillates by negative feedback, and that this oscillation is important for proliferation of neural stem cells, as sustained Hes1 expression inhibits proliferation of these cells. Hes1 oscillation drives the cyclic expression of proneural factors such as Asd1/Mash1. During neuronal differentiation, Hes1 expression disappears and proneural factor expression becomes sustained. By contrast, during astrocyte differentiation, Hes1 expression becomes dominant while proneural factor expression disappears. These results suggest that the multipotency is a state controlled by multiple oscillating fate-determination factors such as Hes1 and Asd1/Mash1, and that one of them becomes dominant during fate choice. We further showed by optogenetic approach that sustained expression of Asd1/Mash1 promotes neuronal differentiation, whereas oscillatory expression of Ascl1/Mash1 activates proliferation of neural stem cells, suggesting that the expression dynamics is important for the function of fate-determination factors. We also found that the Notch ligand Delta-like1 (Dll1), a downstream of Ascl1/ Mashl and Hesl, is expressed in an oscillatory manner, and that this oscillation is important for Hesl oscillation and proliferation of neural stem cells. These results indicate that the oscillatory expression of these factors in neural stem cells is essential for neural development.
Evolution of Cortical Development
A. Goffinet*
Université catholique de Louvain, Belgium. * Presenting e-mail: andre.goffinet@uclouvain.be
OM&P
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
