The development of the central nervous system depends upon the ability of neural stem and progenitor cells to produce an array of distinct neurons and glia that carry out highly specialized functions in mature neural networks. Errors in this process can result in devastating developmental abnormalities that disrupt the integrity of the nervous system or cause more subtle defects that affect learning, behavior, communication, and movement. In our proposed research, we will investigate the genetic pathways that regulate the formation of motor neurons in the spinal cord during embryonic development. We have recently found that members of the Foxp transcription factor family are progressively expressed as motor neuron differentiation proceeds, beginning with Foxp2 in dividing progenitors, followed by Foxp4 as the cells differentiate, and then Foxp1 in subsets of postmitotic motor neurons. Foxp proteins are required for the development of many tissues in the body and alterations in their function contributes to cancerous growth. Foxps are also broadly expressed throughout the CNS, and their function has been implicated in the development of brain regions associated with language. However, at the cellular and molecular level, the functions of Foxp proteins in the nervous system remain largely unknown. Previously, we have shown that Foxp1 is essential for the formation of the MN subtypes that innervate the limbs and sympathetic nervous system, raising the question of what role(s) do the other Foxp proteins play in neural development? In Aim 1 of the proposed research, we will investigate the actions of Foxp2 and Foxp4 in regulating neuroepithelial integrity and neural stem/progenitor cell maintenance.
In Aim 2, we will test the contributions of each Foxp protein to MN fate specification and differentiation. Through these studies, we will provide important new insights into how motor circuits are formed in developing embryos, and how this process may eventually be recapitulated for the repair of injured or diseased neural tissue. In addition, given the broad expression of Foxps in the nervous system and their association with neurological disorders, we anticipate that our studies will further provide more general information on how this transcription factor family contributes to the formation and function of the CNS. )
Spinal motor neurons are essential for all muscle movements, and the loss of their function underlies several devastating neurodegenerative diseases as well as a failure to recover from spinal cord injuries. Currently, few therapies exist to treat these conditions, though great hope has been placed on using stem cell-derived MNs to replace damaged neurons and restore motor functions, and create cells that could be used to study the pathogenesis of MN diseases in vitro. Through the proposed studies, we will provide important new insights into the key developmental mechanisms that underlie MN formation and significantly advance our understanding of how the full repertoire of motor neuron subtypes may be created from stem cells to build disease models and generate therapeutically beneficial cells. !
|Adams, Katrina L; Rousso, David L; Umbach, Joy A et al. (2015) Foxp1-mediated programming of limb-innervating motor neurons from mouse and human embryonic stem cells. Nat Commun 6:6778|
|Kong, Jennifer H; Yang, Linlin; Dessaud, Eric et al. (2015) Notch activity modulates the responsiveness of neural progenitors to sonic hedgehog signaling. Dev Cell 33:373-87|
|Linares, Anthony J; Lin, Chia-Ho; Damianov, Andrey et al. (2015) The splicing regulator PTBP1 controls the activity of the transcription factor Pbx1 during neuronal differentiation. Elife 4:e09268|
|Niewiadomski, Pawel; Kong, Jennifer H; Ahrends, Robert et al. (2014) Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep 6:168-81|
|Xu, Ben; Hrycaj, Steven M; McIntyre, Daniel C et al. (2013) Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb. Proc Natl Acad Sci U S A 110:19438-43|
|Gaber, Zachary B; Butler, Samantha J; Novitch, Bennett G (2013) PLZF regulates fibroblast growth factor responsiveness and maintenance of neural progenitors. PLoS Biol 11:e1001676|
|Kang, Peng; Lee, Hyun Kyoung; Glasgow, Stacey M et al. (2012) Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 74:79-94|
|Rousso, David L; Pearson, Caroline Alayne; Gaber, Zachary B et al. (2012) Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS. Neuron 74:314-30|
|Wang, Yuan; Kim, Edward; Wang, Xiaojing et al. (2012) ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell 150:816-30|
|Roy, AgnÃ¨s; Francius, CÃ©dric; Rousso, David L et al. (2012) Onecut transcription factors act upstream of Isl1 to regulate spinal motoneuron diversification. Development 139:3109-19|
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