This Program examines the interaction of proliferation and cortical interneuron fate determination and probes the functional consequences of altering interneuron subpopulations. Generating the correct number and subtypes of these neurons is crucial for the development of a normally functioning brain, and Project 2 focuses on the interacting roles of several signaling systems, Notch, Wnt, and Sonic hedgehog (Shh), that critically influence this process.
Aim 1. Notch signaling regulates proliferation and cell fate in many organs, but a role for Notch in interneuron generation by the medial ganglionic eminence (MGE), the source of critical cortical interneuron subpopulations, is not known. We identified the Notch ligand Jagged-1 in a microarray screen for genes differentially expressed in the dorsal versus the ventral MGE, raising the possibility that Notch signaling regulates interneuron fate determination.
In Aim 1, we examine conditional loss of Jagged-1 function in the dorsal MGE. Via interactions with Project 1, we explore abnormalities of cyclin D2 expression that we have identified in preliminary studies with these mutants. Via interactions with Project 3, we will further explore Notch-related alterations in proliferative behavior using live imaging in organotypic slice cultures.
Aim 2. During the first four years of this Program we have shown that the expression of the interneuron fate-determining transcription factor, Nkx2.1, requires Shh signaling during interneuron genesis. We also found that proliferation of Nkx2.1-expressing, MGE progenitors requires """"""""canonical"""""""" Wnt signaling. In the other systems, Shh signaling can be necessary for the expression of Tcf4, an effector of """"""""canonical"""""""" Wnt signaling, that we have shown to be expressed in the subcortical telencephalon. Tcf4, in turn, has been shown to activate the expression of Jagged 1 in non-neural tissue.
In Aim 2 we examine potential interactions of Shh, Wnt, and Notch signaling effectors as they relate to MGE proliferation and interneuron fate. Again, interaction with Projects 1 &3 will be critical for teasing out the mechanisms underlying defects in cell cycle and modes of progenitor division that are generated through our various signaling manipulations. As effectors of all three of these signaling systems, like cortical interneurons themselves, are associated with neurological and neuropsychiatric disease, Project 2 will generate several novel mouse models of selective cortical interneuron losses, one of which is expected to produce an inducible, titratable, and time-limited reduction of interneuron genesis, for detailed investigation by the Neurobehavioral Analysis Core. The overarching goal of this project is to link critical mechanisms in neurogenesis and neural subtype fate with clinically germane aspects of brain function.

Public Health Relevance

Interneuron deficits are implicated in the pathobiology of major neurological and psychiatric illnesses, as are deficits in several, interacting, signaling systems. However, the complexity of the interactions, and the tremendous diversity of subcortical forebrain neuronal fate, have made the study of these interactions rare despite the relevance to neuropsychiatric disease. Project 2 tackles this complexity by combining forces in a Program with PIs who employ cutting edge approaches to address critical issues of how developmental signals regulate fate determination and neuronal output in the ventral forebrain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS048120-08
Application #
8500471
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$644,681
Indirect Cost
$123,598
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Chohan, Muhammad O; Moore, Holly (2016) Interneuron Progenitor Transplantation to Treat CNS Dysfunction. Front Neural Circuits 10:64
Sultan, Khadeejah T; Han, Zhi; Zhang, Xin-Jun et al. (2016) Clonally Related GABAergic Interneurons Do Not Randomly Disperse but Frequently Form Local Clusters in the Forebrain. Neuron 92:31-44
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Xu, Hua-Tai; Han, Zhi; Gao, Peng et al. (2014) Distinct lineage-dependent structural and functional organization of the hippocampus. Cell 157:1552-64
Tyson, Jennifer A; Anderson, Stewart A (2014) GABAergic interneuron transplants to study development and treat disease. Trends Neurosci 37:169-77
Sultan, Khadeejah T; Shi, Wei; Shi, Song-Hai (2014) Clonal origins of neocortical interneurons. Curr Opin Neurobiol 26:125-31
Gilani, Ahmed I; Chohan, Muhammad O; Inan, Melis et al. (2014) Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci U S A 111:7450-5
Mirzaa, Ghayda M; Parry, David A; Fry, Andrew E et al. (2014) De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat Genet 46:510-5
Tan, Xin; Shi, Song-Hai (2013) Neocortical neurogenesis and neuronal migration. Wiley Interdiscip Rev Dev Biol 2:443-59

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