The neural circuits that govern behaviors vital to mammals, such as locomotion and respiration, rely on the ability of motor neurons (MNs) within the spinal cord to establish selective connections with dedicated sets of peripheral and central synaptic targets. Signaling pathways acting along the dorsoventral axis of the neural tube have been shown to determine the early identity of MNs and distinguish this class from other neuronal types within the spinal cord. The subsequent diversification of MNs depends on the actions of approximately 20 Hox transcription factors, which appear to be required at distinct phases of MN differentiation. While Hox genes are essential for MN fate specification, the targets of their activities are not known, nor is it understood how they achieve MN-specificity, given their relatively broad roles in patterning along the rostrocaudal axis. Moreover the factors that determine the expression patterns of Hox proteins in MNs are poorly defined.
In aim1 we will characterize the direct targets of Hox proteins, assess how they are regulated in motor columns, and determine if and how they intersect with MN-specific gene programs.
In aim2 we will dissect the mechanisms of Hox protein specificity in controlling facets of MN identity, focusing on the Hoxc9 protein, a central determinant of MN columnar organization.
In aim3 we will test the hypothesis that the organization of Hox-dependent MN subtype relies on graded activities of Polycomb proteins that ensure proper postmitotic Hox expression patterns. These studies will provide basic insights into the mechanisms through which Hox proteins influence MN differentiation, and should allow for the design of strategies to generate MN subtypes from undifferentiated cells.

Public Health Relevance

One of the major challenges in the neural sciences is to understand how the specificity of connections between neurons and their synaptic targets are established during development. The overall goal of this proposal is to elucidate the developmental programs that define the ability of motor neurons in the spinal cord to make very selective connections with muscle targets. Understanding the steps that determine the intrinsic properties of motor neurons may be essential in designing strategies for generating subtypes of neurons from undifferentiated cells, a critical aspect of modeling motor neuron disease states in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS062822-05A1
Application #
8586798
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2008-07-01
Project End
2018-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$370,781
Indirect Cost
$152,031
Name
New York University
Department
Physiology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Jung, Heekyung; Mazzoni, Esteban O; Soshnikova, Natalia et al. (2014) Evolving Hox activity profiles govern diversity in locomotor systems. Dev Cell 29:171-87
Lacombe, Julie; Hanley, Olivia; Jung, Heekyung et al. (2013) Genetic and functional modularity of Hox activities in the specification of limb-innervating motor neurons. PLoS Genet 9:e1003184
Boucherat, Olivier; Montaron, Severine; Berube-Simard, Felix-Antoine et al. (2013) Partial functional redundancy between Hoxa5 and Hoxb5 paralog genes during lung morphogenesis. Am J Physiol Lung Cell Mol Physiol 304:L817-30
Philippidou, Polyxeni; Dasen, Jeremy S (2013) Hox genes: choreographers in neural development, architects of circuit organization. Neuron 80:12-34
Jung, Heekyung; Lacombe, Julie; Mazzoni, Esteban O et al. (2010) Global control of motor neuron topography mediated by the repressive actions of a single hox gene. Neuron 67:781-96