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Organogenesis and Neurogenesis
Yoshiki Sasai M.D., Ph.D.

The complexity of the fully formed brain defies description, yet this organ arises from a nondescript clump of cells in the embryo. The specification of the dorsal-ventral (back-belly) axis is significant in neural development in that the central nervous system forms on the dorsal side of the body in all vertebrate orders. This process is dictated by the effects of a number of signaling factors that diffuse from organizing centers and direct dorsal ectoderm to maintain a neural fate. These molecules, which include Noggin, Chordin, Follistatin and their homologs, participate in elaborate signaling networks in which factors collaborate and compete to initiate the embryonic nervous system.
Using the African clawed frog, Xenopus laevis , as a model in molecular embryological studies, our group is engaged in clarifying the structure and extent of the signaling networks involved in setting up the dorsal-ventral axis and determining neural fate in the ectoderm. These studies focus on molecules that operate at early stages in embryonic development to lay down a complex of permissive, instructive and inhibitory patterns that determines the growth and differentiation of the brain in its earliest stages of development.
The group is now also actively developing effective methods of inducing neuralization in mammals, work which it is hoped will contribute to basic research by providing in vitro experimental systems for use in the analysis of mammalian neurogenesis. In addition, this approach has potential for applications in the treatment of neurodegenerative disorders, such as Parkinson disease. Using a system developed in our lab, we have succeeded in inducing mouse and primate embryonic stem (ES) cells to differentiate into a range of specialized neuronal types. The application of similar techniques to human ES cells represents a field of study that, although it remains at quite an early stage, shows immense clinical promise.
By studying very early neurogenesis, and the mechanisms of neuronal differentiation, our lab aims to understand the molecular basis underpinningthe formation of so intricate a system as the mammalian neural network, in the hopes that, by looking at the elegant simplicity of the embryonic brain, it may one day be possible to understand the cellular bases of the mind's activity.


 


















Select references

Kadoshima T, et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A 110.20284-9 (2013)

Inomata H, et al. Scaling of Dorsal-Ventral Patterning by Embryo Size-Dependent Degradation of Spemannfs Organizer Signals. Cell 153 1296-1311(2013)

Nakano T, et al. Self-Formation of Optic Cups and Storable Stratified Neural Retina from Human ESCs. Cell Stem Cell 10.771-85 (2012)

Suga H, et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature 480. 57-62 (2011)

Eiraku M, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472 51-56(2011)

Kamiya D, et al. Intrinsic transition of embryonic stem-cell differentiation into neural progenitors. Nature 470. 503-509 (2011)

Muguruma K, et al. Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nat Neurosci 13 1171-80 (2010)