Our long-term goal is to define gene networks that enable neural stem cells to produce remarkably divergent cell types in CNS development. The combinatorial action of transcription factors is a prevalent strategy to achieve cellular complexity in CNS. However, the mechanisms underlying combinatorial action of transcription factors in controlling the expression of unique set of terminal differentiation genes for a specific cellular identity remain unclear in vertebrate CNS. In this proposal, we wish to tackle this important issue by focusing on the gene networks for the specification of spinal motor neurons, in which the developmental transcription codes are relatively well understood. LIM homeodomain proteins Lhx3 and Isl1 regulate motor neuron specification in combination by forming a hexameric complex, named MN-hexamer. The key hypothesis of this proposal is that MN-hexamer directly controls a battery of genes that control wide aspects of MN identity, including cholinergic neurotransmission, by coordinating the actions of retinoid signal and chromatin modifying enzymes during spinal cord development. We will test this hypothesis using an ensemble of molecular and biochemical methods, genetically engineered embryonic stem cells, chick embryos and mutant mice.
Three specific aims are proposed to dissect the hypothesis;1) To define the target genes of MN-hexamer that assign MN identity. 2) To investigate the regulation of cholinergic neuronal identity by similar hexameric complexes in spinal motor neurons and forebrain cholinergic neurons. 3) To define the role of RA in facilitating MN specification by MN-hexamer. Besides providing crucial insights into the generation of motor neurons and motor circuits, our studies will lay fundamental framework to study gene networks in creating the amazing cellular diversity during CNS development. These studies should also provide new tools for developing therapeutic strategies for the spinal cord injuries and diseases associated with impaired motor function, such as ALS (Lou Gehrig?s disease), and the cognitive disorders resulting from the loss of forebrain cholinergic neurons, such as Alzheimer?s diseases.

Public Health Relevance

The goal of the proposed research is to understand how the motor neurons are formed during embryonic development. The proper development of motor neurons is essential for our survival, as they coordinate vital movements, such as breathing, walking, and eating. Given that motor neurons are generated only in embryos and hardly regenerate in adults, the proposed studies should provide new opportunities for developing novel strategies to treat diverse motor diseases and injuries.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS054941-09
Application #
8734485
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
Cho, Hyong-Ho; Cargnin, Francesca; Kim, Yujin et al. (2014) Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. PLoS Genet 10:e1004280
Lee, Seunghee; Shen, Rongkun; Cho, Hyong-Ho et al. (2013) STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex. Proc Natl Acad Sci U S A 110:11445-50
Kim, Minchul; Kim, Miju; Lee, Seunghee et al. (2013) cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J 32:1543-55
Lee, Seunghee; Cuvillier, James M; Lee, Bora et al. (2012) Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs. Proc Natl Acad Sci U S A 109:3383-8
Lee, Seunghee; Lee, Jae W; Lee, Soo-Kyung (2012) UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell 22:25-37
Asprer, Joanna S T; Lee, Bora; Wu, Chia-Shan et al. (2011) LMO4 functions as a co-activator of neurogenin 2 in the developing cortex. Development 138:2823-32
Lee, Seunghee; Lee, Soo-Kyung (2010) Crucial roles of histone-modifying enzymes in mediating neural cell-type specification. Curr Opin Neurobiol 20:29-36
Joshi, Kaumudi; Lee, Seunghee; Lee, Bora et al. (2009) LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons. Neuron 61:839-51
Lee, Seunghee; Lee, Bora; Lee, Jae W et al. (2009) Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron 62:641-54
Lee, Seunghee; Lee, Bora; Joshi, Kaumudi et al. (2008) A regulatory network to segregate the identity of neuronal subtypes. Dev Cell 14:877-89

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