LIM-HD/bHLH Combinatorial Code in Motoneurons

Summary

Principal Investigator: Soo Kyung Lee
Abstract: PROJECT SUMMARY 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[unreadable]s disease), and the cognitive disorders resulting from the loss of forebrain cholinergic neurons, such as Alzheimer[unreadable]s diseases.
Funding Period: 2006-04-01 - 2016-08-31
more information: NIH RePORT

Top Publications

  1. pmc The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development
    Jaya Visvanathan
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
    Genes Dev 21:744-9. 2007
  2. pmc STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex
    Seunghee Lee
    Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151 742, Korea
    Proc Natl Acad Sci U S A 110:11445-50. 2013
  3. pmc cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes
    Minchul Kim
    National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology KAIST, Daejeon 305 701, Republic of Korea
    EMBO J 32:1543-55. 2013
  4. pmc Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs
    Seunghee Lee
    Neuroscience Section, Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR 97239, USA
    Proc Natl Acad Sci U S A 109:3383-8. 2012
  5. pmc UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program
    Seunghee Lee
    Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
    Dev Cell 22:25-37. 2012
  6. pmc LMO4 functions as a co-activator of neurogenin 2 in the developing cortex
    Joanna S T Asprer
    Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Development 138:2823-32. 2011
  7. pmc Crucial roles of histone-modifying enzymes in mediating neural cell-type specification
    Seunghee Lee
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Curr Opin Neurobiol 20:29-36. 2010
  8. pmc Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP
    Seunghee Lee
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Neuron 62:641-54. 2009
  9. pmc LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons
    Kaumudi Joshi
    Department of Molecular Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
    Neuron 61:839-51. 2009
  10. pmc A regulatory network to segregate the identity of neuronal subtypes
    Seunghee Lee
    Department of Molecular Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Dev Cell 14:877-89. 2008

Detail Information

Publications11

  1. pmc The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development
    Jaya Visvanathan
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
    Genes Dev 21:744-9. 2007
    ..Our results suggest that, during CNS development, timely down-regulation of SCP1 is critical for inducing neurogenesis, and miR-124 contributes to this process at least in part by down-regulating SCP1 expression...
  2. pmc STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex
    Seunghee Lee
    Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151 742, Korea
    Proc Natl Acad Sci U S A 110:11445-50. 2013
    ..Together, our studies uncover crucial gene regulatory mechanisms that couple MN-hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord. ..
  3. pmc cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes
    Minchul Kim
    National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology KAIST, Daejeon 305 701, Republic of Korea
    EMBO J 32:1543-55. 2013
    ..We also implicate neurofibromin 2 as an AKAP (A-kinase-anchoring protein) scaffold protein that facilitates the function of the cAMP/PKA-LATS-YAP pathway. Our study thus incorporates PKA as novel component of the Hippo pathway...
  4. pmc Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs
    Seunghee Lee
    Neuroscience Section, Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR 97239, USA
    Proc Natl Acad Sci U S A 109:3383-8. 2012
    ..Our studies uncover a highly efficient method for directed MN generation and MN gene networks. Our results also demonstrate a general strategy of using embryonic transcription complexes for producing specific cell types from stem cells...
  5. pmc UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program
    Seunghee Lee
    Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
    Dev Cell 22:25-37. 2012
    ....
  6. pmc LMO4 functions as a co-activator of neurogenin 2 in the developing cortex
    Joanna S T Asprer
    Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Development 138:2823-32. 2011
    ..Our results indicate that LMO4 promotes the acquisition of cortical neuronal identities by forming a complex with NGN2 and subsequently activating NGN2-dependent gene expression...
  7. pmc Crucial roles of histone-modifying enzymes in mediating neural cell-type specification
    Seunghee Lee
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Curr Opin Neurobiol 20:29-36. 2010
    ..Here we discuss the recent advancement in understanding the roles of enzymes involved in histone acetylation and methylation during neural cell-type specification...
  8. pmc Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP
    Seunghee Lee
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Neuron 62:641-54. 2009
    ..Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell fate specification through their synergistic activity to trigger transcriptionally active chromatin...
  9. pmc LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons
    Kaumudi Joshi
    Department of Molecular Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
    Neuron 61:839-51. 2009
    ..Thus, LMO4 plays essential roles in directing a balanced generation of inhibitory and excitatory neurons in the ventral spinal cord...
  10. pmc A regulatory network to segregate the identity of neuronal subtypes
    Seunghee Lee
    Department of Molecular Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Dev Cell 14:877-89. 2008
    ..Thus, our study uncovers a regulatory network to segregate related cell fates, which involves reciprocal feedforward gene regulatory loops...
  11. pmc Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes
    Hyong Ho Cho
    Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Portland, Oregon, United States of America Department of Otolaryngology Head and Neck Surgery, Chonnam National University Medical School, Gwangju, Korea
    PLoS Genet 10:e1004280. 2014
    ....

Research Grants30

  1. TRANSCRIPTIONAL REGULATION BY GEMININ
    Kristen L Kroll; Fiscal Year: 2013
    ..They will inform our understanding of birth defects and provide an essential foundation for manipulating these regulatory networks to control neural cell specification in many biological contexts. ..
  2. The Regulatory Role of the Limk1/Cofilin Signaling Pathway in Spinal Motor Neuron
    Michele Frendo; Fiscal Year: 2013
    ..The ability to intrinsically accelerate axon extension from ESC-derived MNs may lead to more efficient recovery times when paired with other axon regeneration therapies. ..
  3. Extracellular Matrix Signaling in Axon Outgrowth and Regeneration
    Jesse Isaacman-Beck; Fiscal Year: 2013
    ..Together these experiments will define ECM mediated guidance pathways necessary for the development and reconstitution of neuromuscular connections. ..
  4. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  5. Function and dysfunction of brain networks for the flexible expression of memory
    Xiaojing Wang; Fiscal Year: 2013
    ....
  6. Slit and Robo Signaling in the Specification of Motor Neuron Position
    NEAL DILIP AMIN; Fiscal Year: 2013
    ..Taken together, these proposed studies will help uncover fundamental mechanisms by which Slit and Robo are able to specify motor neuron settling position, a critical determinant of synaptic connectivity in the spinal cord. ..
  7. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  8. Molecular control of neurogenesis in the adult subventricular zone
    Masato Nakafuku; Fiscal Year: 2013
    ..Thus, the outcomes of the proposed research will have significant contribution to the promotion of human health and welfare. ..
  9. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  10. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  11. Molecular Mechanisms of SOD1-linked ALS (P01)
    Joan Selverstone Valentine; Fiscal Year: 2013
    ..This project addresses this question for ALS in particular using some of the best advanced biophysical and biochemical methods available. ..
  12. Transplantation of Neural Progenitors as Functional Relay for Spinal Cord Injury
    PENGZHE LU; Fiscal Year: 2013
    ..Further, this model system will provide a rich opportunity for identifying molecular mechanisms underlying axonal regeneration. The goals of this research are directly and highly relevant to the VA patient care mission. ..
  13. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  14. Regulation and Function of Ascl1 in Neural Development
    Jane E Johnson; Fiscal Year: 2013
    ..co-factors that modulate its activity and the gene programs it regulates will provide key entrance points for improving the efficiency of generating specific types of neurons in vitro and in vivo, and for targeting tumor generating cells ..
  15. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  16. Molecular Controls over Induction of Neurogenesis for Brain Repair
    Jeffrey D Macklis; Fiscal Year: 2013
    ..Together, these experiments will significantly advance our ability to induce type-specific neurogenesis and ultimately direct functional circuit repair of the adult CNS. ..
  17. Biology and Novel Therapeutics of Cardiovascular Peptides
    John C Burnett; Fiscal Year: 2013
    ..Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease. ..
  18. Calcium signaling in neuronal navigation
    Guo li Ming; Fiscal Year: 2013
    ..Findings from these studies may lead to novel strategies to functionally replace damaged or lost neurons and to promote endogenous repair after injury or degenerative neurological disease. ..
  19. Proliferation, Specification &Brain Function
    MARGARET ELIZABETH ROSS; Fiscal Year: 2013
    ..This Program tackles this complexity through the combined efforts of 4 Pis using cutting edge approaches to the elucidation of how developmental signals regulate fate and output of these critically important neurons. ..
  20. Genetic Control of Motor Neuron Development and Function
    Samuel L Pfaff; Fiscal Year: 2013
    ..Our studies should provide novel information about the molecular pathways that operate to control motor neuron specification, axon navigation, circuit formation, and survival in adults. ..