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Simon HippenmeyerGenetic Dissection of Cerebral Cortex Development using Mosaic Analysis with Double Markers (MADM)

Abstract :

The cerebral cortex, seat of our cognitive abilities, is composed of an intricate network of interconnected neurons.
The cortical cytoarchitecture consists of distinct layers with different cellular composition and function but the precise mechanisms how these neurons coalesce into defined laminae during development are not well understood. In a pursuit to obtain in-depth insights we study corticogenesis at unprecedented single cell resolution using the genetic MADM (Mosaic Analysis with Double Markers) strategy. MADM technology offers an unparalleled approach to visualize and concomitantly manipulate sparse clones or subsets of genetically defined neurons in mice. Recently, we have expanded the MADM toolkit and inaugurated functional gene analysis with a focus on cortical projection neuron migration and development. These MADM analyses revealed novel insights into the role of the evolutionarily conserved Lis1/Ndel1 complex in cortical projection neuron migration: Lis1 controls migration efficiency whereas Ndel1 regulates a very specific step in the migratory process – invasion into the target lamina. In addition to these cell-autonomous functions of Lis1 and Ndel1, significant non-autonomous effects seem critical. Thus, the balanced interplay of cell-autonomous and non-autonomous functions of candidate signaling molecules controls the sequential steps of cortical projection neuron migration. Altogether, our studies aim to contribute to our understanding of the fundamental cellular and molecular mechanisms underlying the essential neurodevelopmental processes that control cortex assembly.

Selected publications

Liang, H., Xiao, G., Yin, H., Hippenmeyer, S., Horowitz, JM. & Ghashghaei, HT. (2012). Neural Development is Dependent on the Function of Specificity Protein 2 in Cell Cycle Progression. Development, in press.

Liang, H., Hippenmeyer, S., & Ghashghaei, HT. (2012). A Nestin-Cre Transgenic Mouse is Insufficient for Recombination in Early Neural Progenitors. Biology Open, in press.

Tasic, B.*, Miyamichi, K.*, Hippenmeyer, S.*, Dani, VS., Zeng, H., Joo, W., Zong, H., Chen-Tsai, Y. & Luo, L. (2012). Extensions of MADM (Mosaic Analysis with Double Markers) in mice. (*equal contribution). PLoS ONE, 7(3): e33332.

Liu, C., Sage, JC.*, Miller, MR.*, Verhaak, RGW.*, Hippenmeyer, S., Vogel, H., Foreman, O., Bronson, RT., Nishiyama, A., Luo, L. & Zong, H. (2011). Mosaic Analysis with Double Markers

Reveals Tumor Cell of Origin in Glioma. (*equal contribution). Cell, 146 (2): 209-21. Evaluated by Faculty of 1000: Preview by Sukhdeo, K., Hambardzumyan, D. & Rich, JN. (2011).

Glioma Development: Where Did It All Go Wrong? Cell 146 (2): 187-8. Commentary by Alderton, GK. (2011). Tumorigenesis - The Origins of Glioma. Nature Reviews Cancer 11 (9): 628.

Scientific focus :

A core interest of our research is the dissection of the cellular, molecular and epigenetic mechanisms of neuronal development using interdisciplinary experimental approaches. Currently, we exploit the unique genetic methodology called MADM (Mosaic Analysis with Double Markers) to dissect the fundamental principles controlling the development and assembly of the cerebral cortex in the mouse. With MADM it is for the first time possible to generate and visualize genetic mosaics allowing the functional analysis of virtually any gene in the whole mouse genome at unprecedented cellular resolution. By using this unparalleled approach we determine the molecular mechanism regulating neurogenesis and neuronal migration in the cortex, and analyze the cellular pathology associated with genes that when mutated in human cause severe neurodevelopmental disorders. In a second line of research we explore genomic imprinting (an epigenetic phenomenon) and its role in neurodevelopment.

Nathalie SANS du Neurocentre