The neural circuits governing motor functions vital to mammals, including walking and breathing rely on the ability of spinal motor neurons (MNs) to acquire specific subtype identities and establish selective connections with 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 ~20 Hox transcription factors, which orchestrate genetic programs essential for MN organization, identity, and connectivity. During development, expression of Hox genes is induced through the actions of secreted morphogens which act though removing repressive chromatin marks from Hox clusters. These repressive marks are established and maintained through the actions of the large family of Polycomb group (PcG) proteins. Although removal of Polycomb repressive marks is associated with the activation of specific Hox genes, the functions and mechanisms of action of these complexes are poorly understood.
In Aim1 we will examine the effects of removal of Polycomb repressive complex 1 (PRC1) activities from MNs, through selective genetic ablation of Ring1 genes.
In Aim2 we will determine the targets of PRC1 actions, focusing on Hox genes, and assess how misregulation of PRC targets affects MN differentiation.
In Aim3 we will explore the hypothesis that distinct PRC1 configurations determine the organization and identity of MN subtypes through differentially regulating Hox genes along the rostrocaudal axis. These studies should provide basic insights into the mechanisms by which chromatin modifications influence neural specification. Understanding the mechanisms of PcG protein function could improve the current strategies for generating MN subtypes from undifferentiated cells.
The overall goal of this proposal is to elucidate the mechanisms that enable neuronal progenitors to acquire specific cell fates during development. These studies will investigate the role of histone modifying protein complexes in regulating the expression of cell fate determinants in spinal motor neurons. Understanding the steps that determine how chromatin modifications within the genome enable motor neurons to differentiate may be critical in designing strategies for generating specific neuronal subtypes from undifferentiated cells, an essential facet of modeling motor neuron disease states in vitro.
Showing the most recent 10 out of 16 publications
