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.
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.
|Lee, Bora; Lee, Seunghee; Lee, Soo-Kyung et al. (2016) The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons. Development 143:3763-3773|
|Thiebes, Karen P; Nam, Heejin; Cambronne, Xiaolu A et al. (2015) miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1-Lhx3. Nat Commun 6:7718|
|Kim, Dae-Hwan; Rhee, Jennifer Chiyeon; Yeo, Sujeong et al. (2015) Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice. Hepatology 61:1012-23|
|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, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan et al. (2013) Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor. Mol Cell Biol 33:3826-34|
|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, Bora; Kim, Sun-Gyun; Kim, Juhee et al. (2013) Brain-specific homeobox factor as a target selector for glucocorticoid receptor in energy balance. Mol Cell Biol 33:2650-8|
|Kim, Dae-Hwan; Tang, Zhanyun; Shimada, Miho et al. (2013) Histone H3K27 trimethylation inhibits H3 binding and function of SET1-like H3K4 methyltransferase complexes. Mol Cell Biol 33:4936-46|
|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|
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