Person: Woodworth, Mollie Ann
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Woodworth
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Mollie Ann
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Woodworth, Mollie Ann
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Publication Molecular logic of neocortical projection neuron specification, development and diversity(Nature Publishing Group, 2013) Greig, Luciano Custo; Woodworth, Mollie Ann; Galazo, Maria; Padmanabhan, Hari; Macklis, JeffreyThe sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation. In recent years, several key controls over the specification and differentiation of neocortical projection neurons have been identified. This work provides substantial insight into the 'molecular logic' underlying cortical development and increasingly supports a model in which individual progenitor-stage and postmitotic regulators are embedded within highly interconnected networks that gate sequential developmental decisions. Here, we provide an integrative account of the molecular controls that direct the progressive development and delineation of subtype and area identity of neocortical projection neurons.Publication Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers(Elsevier BV, 2016) Woodworth, Mollie Ann; Greig, Luciano C.; Liu, Kevin; Ippolito, Gregory C.; Tucker, Haley O.; Macklis, JeffreyThe molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons, but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections.Publication Ctip1 Controls Acquisition of Sensory Area Identity and Establishment of Sensory Input Fields in the Developing Neocortex(Elsevier BV, 2016) Greig, Luciano C.; Woodworth, Mollie Ann; Greppi, Chloe; Macklis, JeffreyWhile several transcriptional controls over the size and relative position of cortical areas have been identified, less is known about regulators that direct acquisition of area-specific characteristics. Here, we report that the transcription factor Ctip1 functions in primary sensory areas to repress motor and activate sensory gene expression programs, enabling establishment of sharp molecular boundaries defining functional areas. In Ctip1 mutants, abnormal gene expression leads to aberrantly motorized corticocortical and corticofugal output connectivity. Ctip1 critically regulates differentiation of layer IV neurons, and selective loss of Ctip1 in cortex deprives thalamocortical axons of their receptive “sensory field” in layer IV, which normally provides a tangentially and radially defined compartment of dedicated synaptic territory. Therefore, although thalamocortical axons invade appropriate cortical regions, they are unable to organize into properly configured sensory maps. Together, these data identify Ctip1 as a critical control over sensory area development.Publication Transcriptional Controls over Neocortical Projection Neuron Identity and Connectivity(2013-03-18) Woodworth, Mollie Ann; Macklis, Jeffrey Daniel; Corfas, Gabriel; Arlotta, Paola; He, Zhigang; Cepko, Constance; Sanes, Joshua; Hevner, RobertThe complex and sophisticated circuitry of the neocortex is assembled from an extraordinarily diverse repertoire of neuronal subtypes that reside in distinct functional areas. In recent years, a number of key regulators over neocortical projection neuron subtype and area specification have been identified. It is becoming increasingly clear that these regulators function within a highly-interconnected network, acting in parallel, synergistically, and cross-repressively to orchestrate cortical development. Moreover, an emerging understanding of cortical development has revealed that subtype and area identity are intimately interrelated, and that specification occurs based on several sequential molecular decision points. Although great strides have been made in recent years toward understanding molecular controls over neocortical projection neuron development, many important controls remain to be discovered, and mechanisms by which recently-identified regulators act to delineate subtype and area identity are not well understood. In this dissertation, I characterize functions of two zinc finger transcription factors, Ctip2 and Ctip1, in postmitotic projection neuron subtype and area identity acquisition, using in vivo gain- and loss-of-function approaches in the mouse. I find that Ctip2, known for several years as a central functional control over corticospinal motor neuron (CSMN) terminal differentiation and connectivity, is required both cell-autonomously (within CSMN) and non-cell-autonomously (within striatal medium-sized spiny neurons that surround CSMN axons traveling in the internal capsule) for CSMN to achieve proper connectivity with the spinal cord. In addition, I find that Ctip1, a transcription factor not previously functionally investigated in neocortical development, is a novel control over 1) corticothalamic and callosal projection neuron development and projection neuron migration; and 2) postmitotic area identity acquisition and the formation of sensory maps. Taken together, these results reveal previously unknown functions of Ctip1 in neocortical development, and novel sites of action for Ctip2 control over CSMN connectivity. Ctip1 and Ctip2 are transcriptional controls over the postmitotic specification of neocortical projection neuron subtype and area identity, and over projection neuron connectivity with distant targets.