Considerable progress has been made in defining the transcriptional events that control the stepwise Differentiation of unspecified neural precursors into motor neurons that innervate specific muscle targets. Despite these advances, much remains to be learned of the transcriptional regulatory network that subtends this process. Based on the ability to generate homogeneous preparations of specific motor neuron subtypes from ES cells, this project will take a global approach to defining transcriptional differences between motor neurons and other spinal neurons. Transcription factors identified will then be used to identify target genes and thereby iteratively define transcriptional networks. The work is structured around three aims.
Aim 1. will use transcription factors known to determine motor neuron or dorsal interneuron fate to drive ES cell differentiation, in order to identify factors potentially involved in the acquisition of generic motor neuron identity.
Aim 2. will use intrinsic and extrinsic factors that drive the differentiation of motor neurons characteristic of specific columns or pools from mouse ES cells, to define the transcrptional logic that controls motor neuron subtype identity. These basic advances will be applied in Aim 3. to the study of Spinal Muscular Atrophy (SMA), a developmental disease that results from reduction in levels of a protein, SMN, that is required for motor neuron survival. New ES cell lines will be derived from motor neurons expressing normal and reduced levels of SMN, obtained from mouse models for SMA. These disease-specific ES cells will be screened for differences in transcriptional repertoire. Functional testing of genes identified as potential effectors in these screens will be performed using a panel of in vitro and in vivo test systems focused on motor neuron differentiation, survival and axon growth. The project should also provide new approaches to potential therapeutic targets in SMA. Relevance Studying the way in which specific groups of motor neurons in the spinal cord develop to innervate specific muscles is central to understanding how precise control of breathing and movement is achieved. These studies will provide clues for understanding why specific groups of motor neurons degenerate and die in patients with diseases such as spinal muscular atrophy (SMA). This project will identify molecular mechanisms involved both in normal development and pathologic degeneration of this important neuronal population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS055923-03
Application #
7684165
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$184,904
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Zeng, Haoyang; Edwards, Matthew D; Liu, Ge et al. (2016) Convolutional neural network architectures for predicting DNA-protein binding. Bioinformatics 32:i121-i127
Arbab, Mandana; Sherwood, Richard I (2016) Self-Cloning CRISPR. Curr Protoc Stem Cell Biol 38:5B.5.1-5B.5.16
Hashimoto, Tatsunori; Sherwood, Richard I; Kang, Daniel D et al. (2016) A synergistic DNA logic predicts genome-wide chromatin accessibility. Genome Res 26:1430-1440
Barkal, Amira A; Srinivasan, Sharanya; Hashimoto, Tatsunori et al. (2016) Cas9 Functionally Opens Chromatin. PLoS One 11:e0152683
Arbab, Mandana; Srinivasan, Sharanya; Hashimoto, Tatsunori et al. (2015) Cloning-free CRISPR. Stem Cell Reports 5:908-917
Mahony, Shaun; Edwards, Matthew D; Mazzoni, Esteban O et al. (2014) An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding. PLoS Comput Biol 10:e1003501
Sherwood, Richard I; Hashimoto, Tatsunori; O'Donnell, Charles W et al. (2014) Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape. Nat Biotechnol 32:171-178
Wichterle, Hynek; Gifford, David; Mazzoni, Esteban (2013) Neuroscience. Mapping neuronal diversity one cell at a time. Science 341:726-7
Mazzoni, Esteban O; Mahony, Shaun; Closser, Michael et al. (2013) Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nat Neurosci 16:1219-27
Arbab, Mandana; Mahony, Shaun; Cho, Hyunjii et al. (2013) A multi-parametric flow cytometric assay to analyze DNA-protein interactions. Nucleic Acids Res 41:e38

Showing the most recent 10 out of 33 publications