Mollie Woodworth - US grants

DESCRIPTION (provided by applicant): The long-term goals of the proposed experiments are both to elucidate the neuron subtype-specific development of neocortical projection neuron circuitry and to repair diseased neocortical projection neurons. During the development of the mammalian telencephalon, spatially and temporally heterogeneous progenitor cells generate a rich variety of projection neuron subtypes. Although key molecular controls over regionalization of progenitors have been extensively characterized, the investigation of genes regulating projection neuron subtype identity acquisition in postmitotic neurons has only relatively recently begun. Recent work in the Macklis laboratory (Arietta et al., Neuron '05;Molyneaux et al., Neuron '05;Ozdinler and Macklis, Nature Neurosci. '06;Molyneaux et al.. Nature Rev. Neurosci. '07;Arietta et al., J. Neurosci., '08;Lai et al.. Neuron '08;Joshi et al., Neuron '08;Azim et al., '09, Srubeck Tomassy et al., '09), complemented and broadened by work from other investigators, has identified a combinatorial program of transcription factor controls over the specification and differentiation of cortical projection neurons from progenitor cells. One such transcription factor, COUP-TF interacting protein 2 (Ctip2) has been shown by our laboratory to be centrally important for the differentiation of both corticospinal motor neurons (CSMN) (and related subcerebral projection neurons) in the neocortex and medium-sized spiny neurons (MSN) in the striatum;however, the specific molecular differentiation programs executed by Ctip2 in these important neuron types is unknown. In this proposal, I outline a program of research designed to investigate the functions of Ctip2 in CSMN development. I propose to 1) identify the specific role(s) of Ctip2 in CSMN axon extension and fasciculation;2) delineate the specific role(s) of Ctip2 in CSMN axon pathfinding;and 3) investigate a possible interaction between Ctip2 and its family member Ctipl in the developing cortex. These studies will elucidate the mechanisms by which Ctip2, a central regulator of CSMN identity, acts alone and in concert with other genes to instruct the development of this clinically important neuron type. The proposed research has significant clinical implications. As CSMN are the brain neurons that degenerate in amyotrophic lateral sclerosis (ALS), and a central population damaged in spinal cord injury, a detailed understanding of the program of genetic controls regulating the generation and maturation of this specific projection neuron population is important both for fundamental understanding of brain organization and function, and for the potential future development of cellular repair strategies for ALS, spinal cord injury, and other diseases affecting CSMN.

Project Summary/Abstract Vision loss is a devastating medical problem that generates significant medical costs, directly as well as indirectly in the form of decreased productivity, lower quality of life, and loss of independence among those affected. In the United States, disorders of the eye result in a significant economic burden for society. Because the human retina has minimal or no regenerative ability, loss of retinal neurons due to intrinsic defects or environmental insults is generally irreversible, making this the most common cause of permanent visual impairment. In this project, the candidate proposes to study the development of retinal ganglion cells, the output projection neurons that connect the eye with the brain. These neurons are vulnerable to injury in traumatic optic nerve injuries and to diseases such as glaucoma, and a deeper understanding of their development and regeneration could have significant implications for reversing visual impairment. In the first part of this application, the candidate proposes to investigate the function of a transcription factor expressed by retinal ganglion cells in a mouse line with this gene conditionally deleted, and by using overexpression in retinal progenitor cells in vivo. In the second part of this application, the candidate proposes to screen a candidate list of transcription factors by overexpression in vivo for their ability to reprogram endogenous retinal cells to produce new retinal ganglion cells. Overall, insights from the study of normal retinal ganglion cell development will be applied to develop methods for replacing these cells when they are damaged or diseased. The candidate?s overall career goal is to understand developmental processes that shape the nervous system, and to apply this developmental knowledge to regenerate neurons lost to injury or disease. The candidate has a deep background in cerebral cortical developmental biology and proposes to receive training in retinal development because the retina is significantly more accessible to clinical manipulation, and promising regenerative therapies are already beginning to come to fruition. During the mentored phase of this award, the candidate will prioritize undertaking activities to increase understanding of retinal development, to do productive and meaningful science, and consequently to transition research from cerebral cortical development to retinal development. The PI will work with mentors Dr. Jeffrey Goldberg and Dr. Sui Wang, together with members of a Stanford faculty advisory team. The proposed research and training plans will take place in the laboratory of Dr. Jeffrey Goldberg, chair of the Department of Ophthalmology at Stanford University School of Medicine. The outstanding vision science group at Stanford is embedded within the world-class neuroscience and broader life sciences community at Stanford as a whole, with benefits of a close-knit and focused department and the resources of the wider university.