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Transcriptional regulatory network in CNS development
Our long-term research goal is to decode the combinatorial transcriptional regulatory network responsible for generating distinct classes of neurons that perform sensory and
motor functions in the developing central nervous system (CNS). We utilize an ensemble of cellular models, extensive mouse genetic mutants, gain and loss of functional studies in chick
embryos, molecular methods and biochemical approaches.
First, we characterize a series of important enhancer and silencer elements from genes specifically expressed in distinct neuronal subtypes. These studies, coupled with bioinformatics as well
as DNA microarrays, serve as powerful tools to investigate the detailed combinatorial code of transcription factors and their regulatory circuits in cell type specification.
Second, we dissect the function of a number of transcriptional coregulatory proteins involved with cell type specification. Although much attention has been paid to define the function of
transcription factors in neuronal specification, very little is known about the role of transcriptional coregulators during the CNS development. Thus, we have developed multiple mouse lines
in which transcriptional cofactor genes are selectively deleted in embryonic CNS and been analyzing their CNS phenotypes.
Finally, we apply the differential regulatory circuits defined above to various stem cells in an effort to generate specific neurons at will. For instance, we have recently succeeded
generating motor neurons from multi-potent embryonic stem cells. These studies will provide invaluable cellular model systems that should enable further studies of the CNS development through
in vitro functional assays as well as different biochemical approaches.
Overall, our studies should provide critical insights into the basic principles involved with the proper formation of the nervous system as well as practical information for treatments of a
variety of neuronal injuries and diseases.
Selected Publications
Lee SK, Pfaff SL (2001) Transcriptional networks regulating neuronal identity in the developing spinal cord. Nature Neuroscience 4:1183-1191.
Thaler JP*, Lee SK*, Jurata LW*, Gill GN, Pfaff SL (2002) LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through
cell-type-specific protein-protein interactions. Cell 110:237-249. (*Equal contribution)
Lee SK, Pfaff SL (2003) Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors. Neuron
38:731-745.
Lee SK, Jurata LW, Funahashi J, Ruiz EC, Pfaff SL (2004) Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with
enhancer factors. Development 131:3295-3306.
Lee SK, Lee B, Ruiz EC, Pfaff SL (2005) Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells. Genes and Development
19:282-294.
Yeo M*, Lee SK*, Lee B, Ruiz EC, Pfaff SL, Gill GN (2005) Small CTD phosphatases function in silencing neuronal gene expression. Science 307:596-600.
(*Equal contribution)
Song MR, Shirasaki R, Cai CL, Ruiz EC, Evans SM, Lee SK, Pfaff SL (2006) T-Box transcription factor Tbx20 regulates a genetic program for cranial motor neuron cell body
migration. Development 133:4945-4955.
Lee S, Lee DK, Dou Y, Lee J, Lee B, Kwak E, Kong YY, Lee SK, Roeder RG, Lee JW (2006) Coactivator as a target gene specificity determinant for histone H3 lysine
4 methyltransferases. Proceedings of the National Academy of Sciences U.S.A. 103:15392-15397.
Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes
and Development 21:744-749.
Lee S, Lee B, Joshi K, Pfaff S, Lee JW, Lee SK (2008) A novel regulatory network to segregate spinal neuronal identities. Developmental Cell, in press.
Contact Information
- Soo-Kyung Lee, Ph.D.
- Department of Molecular and Cellular Biology
- Huffington Center on Aging
- Baylor College of Medicine
- One Baylor Plaza 132C
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-8524
- Fax: (713) 798-0545
- E-mail: sklee@bcm.edu
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