Surprisingly little is known about the molecular histogenesis of the mammalian CNS, due in part to the inaccessibility of the early embryo for direct manipulation. Our research has focused on the role of the BMP signaling cascade in this process using embryonic stem (ES) cells as a model of the events involved in lineage segregation, followed by studies in the intact embryo. Since the gene expression profile of ES cells is similar to the inner cell mass and the epiblast and they are poised to undergo multi-lineage differentiation, ES cells can be a powerful model system to tease out the successive waves of gene expression and inhibition that shape the early embryo.
 Our research is focused on the very early histogenesis of the primitive nervous system—from neural induction through neurulation and neurogenesis. In one project, we are using both mouse and human embryonic stem (ES) cells to examine the roles of BMP, Wnt and FGF signaling, the role of the bHLH neural determination genes, neurogenins and their inhibitors, the Id genes in the neuronal differentiation of pluripotent ES cells. Related work involves targeted mis-expression of these molecules using transgenesis and RNAi treatment of whole embryos.
(Human ES cells exposed to noggin differentiate into primitive neurons).
 We have recently identified a panel of novel genes induced in ES cells by noggin exposure that may play a role in stabilizing the phenotype of early induced neural ectoderm cells—the elusive intermediate between induction of neural ectoderm from epiblast and neural differentiation. Several of these novel genes are expressed in provocative patterns in the early embryo in the node or early neural ectoderm. These are being examined further using in situ hybridization localization and knock-down of gene expression using transplacental RNA interference (RNAi). There are also a number of candidate genes that are strongly down-regulated by noggin expression that might play a role in maintaining pluripotency of ES cells and/or inhibiting their differentiation.
(Expression of a noggin-induced gene in the node (arrowhead) and neural ectoderm).
Another research project involves the molecular dissection of the neural stem cell niche, which appears to be controlled by BMP signaling—BMP4 from type B progenitorr cells and noggin from ependymal cells. This work examines the ability of prenatally delivered RNAi targeted to BMP4 to promote neuronal differentiation of neural stem cells, inducible expression of noggin in progenitor cells in the niche, and selective ablation of progenitors. The long term goal of this work is to determine the role of noggin in the development and response of the nervous system to injury. Ultimately cell fate, region specific differentiation, and integration of neural cells into the CNS may depend on local cues made available via the extracellular matrix. Our lab also has a longstanding interest in the role of the ECM, particularly the thrombospondins in promoting neural differentiation, repair, process outgrowth and cell migration.
Recent Publications:
- Gratsch TE, O’Shea KS. Noggin and chordin have distinct activities in promoting lineage commitment of mouse embryonic stem (ES) cells. Developmental Biology 2002, 245: 83-94.
- Velkey JM, O’Shea KS. Oct4 RNA interference induces trophectoderm differentiation in mouse embryonic stem cells. genesis, 2003, 37: 18-24.
- O’Shea KS. Models for neural development and clinical disorders, In: Bottenstein J (Ed), Neural Stem Cells: Development and Transplantation. New York: Kluwer Publishers, 2003, pp 1-54.
- Gratsch TE, De Boer LS, O’Shea KS. RNA interference of BMP-4 gene expression in postimplantation mouse embryos. genesis, 2003, 37: 12-17.
- Lorincz MT , Detloff PJ, Albin RL, O’Shea KS. Embryonic stem cells expressing expanded CAG repeats undergo aberrant neuronal differentiation and have persistent Oct-4 and REST/NRSF expression. Molecular and Cellular Neuroscience, 2004, 26: 135-143.
- O’Shea KS. MINIREVIEW: Self-renewal vs differentiation of mouse embryonic stem cells. Biology of Reproduction, 2004, in press.
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