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Faculty
Kristin Baldwin
Assistant Professor
Department of Cell Biology
TSRI - 2006
Education
Ph.D. Stanford University, Immunology 1998
B.S. Duke University, Economics 1991
Research Focus
Advancing Stem Cell Technology to Study Genomes and the Brain:
Generating Mice from iPS Cells: During development, undifferentiated stem cells generate the millions of distinct cell types in the body in a choreographed sequence that is unidirectional. Until recently, differentiated mammalian cells were thought to have irreversibly lost the ability to generate less differentiated cell types, for unknown reasons. Thus embryonic stem cells and somatic stem cells were assumed to be unique resources to generate more differentiated cell types in vitro. Reprogramming by transient expression of pluripotency factors can restore differentiated cells to a state of developmental potency that resembles embryonic stem (ES) cells, however, the first generations of induced pluripotent stem (iPS) cells differed from ES cells in that they could not generate live adult mice. We recently developed a reprogramming method that restores differentiated fibroblasts to full pluripotency such that we can produce live mice derived entirely from differentiated cells, without using oocytes. These fully pluripotent iPS cells and iPS mice allow us to examine the functional stability of iPS derived tissues and to probe the genomic stability of differentiated cells. Applying this technology to human cells should allow us to generate improved iPS cell lines. One goal is to use these cells to generate improved models of disease, in particular, inherited human neurological diseases for which no in vitro models exist.
Generating Cell Lines from Neurons: Brains are composed of an extraordinary diversity of neurons, which are primarily generated at birth and are maintained without cell division for the life of an individual. Neurons do not divide and have not been shown to generate tumors, for unknown reasons. The inability to generate cell lines from neurons precludes a number of important studies including analyses of neuronal genomic stability in differentiation and disease, and has impeded the generation of appropriate in vitro models of disease. Previously we were the first to generate cloned mice and ES cell lines from differentiated olfactory sensory neurons using reprogramming by nuclear transfer. A current goal is to generate cell lines from neurons to identify unknown irreversible changes to neuronal DNA and to generate the best possible models of neurological diseases such as autism, schizophrenia, Parkinson’s disease and developmental diseases arising from inherited defects in genome maintenance and epigenetic alterations.
Generating Neuronal Diversity and Connectivity in the Olfactory System. Exciting recent advances in stem cell technology that suggest it may be possible to generate neurons in vitro to model disease or for use in cell replacement therapy. However, little is known about the extent of genetic diversity of neurons of the same subtype, or how diverse neurons are wired together to form a functional neuronal circuit. We exploit the genetic tractability and anatomic stereotypy of the olfactory system to generate gene targeted mice in which we can label and modify specific neuronal circuits involved in detecting smells. We are currently mapping the links between the nose and cortical brain regions involved in responding to odors. Identifying the patterns of gene expression and synaptic connectivity of defined neuronal populations will be important to assess the potential utility of iPS derived neurons in vitro and in transplantation experiments and should shed light on design principles of functional neuronal circuits.
Selected References
*Boland MJ, *Hazen JL, *Nazor K, Rodriguez AR, Gifford W, Martin G, Kupriyanov S, and Baldwin KK. Adult mice generated from induced pluripotent stem cells. Nature. 03 September 2009. 46:91-96. * these authors contributed equally.
*Eggan, K., *Baldwin, K., Tackett, M., Osborne
, J., Gogos, J., Chess, A., Axel, R. and Jaenisch, R. Mice cloned from olfactory sensory neurons. Nature. 04 March 2004. 428: 44-49. * these authors contributed equally.
*Tasic, B., *Nabholz, C.E., Baldwin, K., Kim, Y., Rueckert, E.H., Ribich, S.A., Cramer, P., Wu, Q., Axel, R. and Maniatis, T. Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. Molecular Cell. 2002. 10(1): 21-33. * these authors contributed equally.
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