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.
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.
|Catela, Catarina; Shin, Maggie M; Lee, David H et al. (2016) Hox Proteins Coordinate Motor Neuron Differentiation and Connectivity Programs through Ret/GfrÎ± Genes. Cell Rep 14:1901-15|
|Hanley, Olivia; Zewdu, Rediet; Cohen, Lisa J et al. (2016) Parallel Pbx-Dependent Pathways Govern the Coalescence and Fate of Motor Columns. Neuron 91:1005-20|
|Dasen, Jeremy S (2016) Master or servant? emerging roles for motor neuron subtypes in the construction and evolution of locomotor circuits. Curr Opin Neurobiol 42:25-32|
|Jung, Heekyung; Dasen, Jeremy S (2015) Evolution of patterning systems and circuit elements for locomotion. Dev Cell 32:408-22|
|Jung, Heekyung; Mazzoni, Esteban O; Soshnikova, Natalia et al. (2014) Evolving Hox activity profiles govern diversity in locomotor systems. Dev Cell 29:171-87|
|Boucherat, Olivier; Montaron, SÃ©verine; BÃ©rubÃ©-Simard, FÃ©lix-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|
|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|
|Philippidou, Polyxeni; Walsh, Carolyn M; Aubin, JosÃ©e et al. (2012) Sustained Hox5 gene activity is required for respiratory motor neuron development. Nat Neurosci 15:1636-44|
|Golden, Molly G; Dasen, Jeremy S (2012) Polycomb repressive complex 1 activities determine the columnar organization of motor neurons. Genes Dev 26:2236-50|
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