Inhibitory cortical interneurons, most originating in the medial ganglionic eminence (MGE), are part of virtually every cortical circuit. Normal cortical function critically depends on generating these GABAergic cells in numbers and subtypes in proper proportion to excitatory projection neurons. This requires exquisite coordination of progenitor subtype proliferation with differentiation. Project 1 studies the roles of cell cycle constituents in the patterning and function of mammalian brain and showed that two G1-phase active cyclins, cD1 and cD2, are expressed in distinct progenitor subsets in the MGE. Ablation of cD2 results in loss of cortical PV+ but not SST+ interneurons. We hypothesize that cD1 functions to promote asymmetric divisions of radial glial cells, some of which generate SST+ interneurons. In contrast, cD2 may promote the symmetric divisions of intermediate progenitor cells that will primarily generate PV+ interneurons Aim 1. The distinct roles of cD2 vs. cD1 in MGE divisions will be examined using acute overexpression and knockdown of these cyclins in utero, together with analyses of cell position, morphology, and colabeling with markers of proliferative and post-mitotic subpopulations. Via collaboration with Project 3, timelapse imaging in WT, c D I - / - and cD2-/- MGE will examine how loss of cD2 or cD1 affects symmetric vs. asymmetric divisions. We will take advantage of a fluorescence tagging method to compare cell cycle phase duration in cD2-/- vs. cD1-/- MGE. The hypothesis that cD2 expression favors symmetric while cD1 promotes asymmetric divisions will be tested.
Aim 2. The transcriptome of cD2+ MGE progenitors will be investigated using two different approaches to capture RNA from cD2+ MGE cells in transgenic mice;Translating Ribosome Affinity Purification (TRAP) or fluorescence activated cell sorting (FACS) followed by microarray. Data will define the molecular context in which cD2 is operating in the MGE. Interpretation of these arrays will be greatly facilitated by insights from Project 2 studies that have identified a connection between Notch signaling and regulation of cD2 expression in the dorsal MGE, while Wnt and Shh signaling have effects on proliferation, likely upstream of Notch. Thus, potentially meaningful expression patterns will be more readily recognizable.
Aim 3. Inducible cD2-CreER[T2] will be used to map the fate outcomes of cD2+ progenitors while conditional inactivation in Nkx2.1-Cre:cD2fl/fl and Dlx1/2-Cre:cD2fl/fl models will probe contributions of cD2 to interneuron specification. We hypothesize that PV+ interneurons arise primarily from cD2+ progenitors in the SVZ while SST+ interneurons derive primarily from neurogenic divisions in the VZ. Project 2 expertise will be essential as we establish fate maps of MGE-derived cD2+ progenitors. Outcomes of cD2 loss selectively within the MGE on interneuron distribution and function will be tested in the Neurobehavioral Analysis Core, to probe cognitive changes due to loss of these interneuron subsets.
The mechanisms linking cell division to neural specification, particularly in subcortical brain, are appreciated at only a rudimentary level. That VZ and SVZ cells use different cell cycle components and that disturbing this balance can alter the interneuron composition in the cerebral cortex adds to the rich complexity of ways neurogenesis is regulated in the developing brain. This Program brings together 4 laboratories with the advanced capabilities that place us in an unprecedented position to understand the mechanisms regulating genesis of these neuron subtypes that are targets of many neuropsychiatric diseases.
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