Bio

Institute Affiliations


  • Member, Maternal & Child Health Research Institute (MCHRI)

Professional Education


  • Bachelor of Science, Massachusetts Institute of Technology (2006)
  • Doctor of Philosophy, Harvard University (2013)

Research & Scholarship

Current Research and Scholarly Interests


Many types of blindness result from the neurons of the retina no longer being able to communicate with the brain due to injury or disease. In mammals, the adult retina cannot make new retinal ganglion cells (the neurons that connect the retina with the brain) to replace those that are lost. In my work, I aim to learn about normal development of retinal ganglion cells and, further, to regenerate new retinal ganglion cells if they are lost in adulthood.

Publications

All Publications


  • microRNAs Refine Cortical Projection Neuron Subtype during Mammalian Development Siththanandan, V., Diaz, J., Lu, V., Gonzalez-Nava, N., Pasquina, L., MacDonald, J., Woodworth, M., Sahni, V., Sarnow, P., Palmer, T., Macklis, J., Tharin, S. WILEY. 2018: S276?S277
  • Aging and neurodegeneration are associated with increased mutations in single human neurons SCIENCE Lodato, M. A., Rodin, R. E., Bohrson, C. L., Coulter, M. E., Barton, A. R., Kwon, M., Sherman, M. A., Vitzthum, C. M., Luquette, L. J., Yandava, C. N., Yang, P., Chittenden, T. W., Hatem, N. E., Ryu, S. C., Woodworth, M. B., Park, P. J., Walsh, C. A. 2018; 359 (6375): 555?58

    Abstract

    It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.

    View details for DOI 10.1126/science.aao4426

    View details for Web of Science ID 000423795800037

    View details for PubMedID 29217584

    View details for PubMedCentralID PMC5831169

  • Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias CELL REPORTS D'Gama, A. M., Woodworth, M. B., Hossain, A. A., Bizzotto, S., Hatem, N. E., LaCoursiere, C. M., Najm, I., Ying, Z., Yang, E., Barkovich, A., Kwiatkowski, D. J., Vinters, H. V., Madsen, J. R., Mathern, G. W., Blumcke, I., Poduri, A., Walsh, C. A. 2017; 21 (13): 3754?66

    Abstract

    Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

    View details for DOI 10.1016/j.celrep.2017.11.106

    View details for Web of Science ID 000418721800013

    View details for PubMedID 29281825

    View details for PubMedCentralID PMC5752134

  • Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network SCIENCE McConnell, M. J., Moran, J. V., Abyzov, A., Akbarian, S., Bae, T., Cortes-Ciriano, I., Erwin, J. A., Fasching, L., Flasch, D. A., Freed, D., Ganz, J., Jaffe, A. E., Kwan, K. Y., Kwon, M., Lodato, M. A., Mills, R. E., Paquola, A. C., Rodin, R. E., Rosenbluh, C., Sestan, N., Sherman, M. A., Shin, J. H., Song, S., Straub, R. E., Thorpe, J., Weinberger, D. R., Urban, A. E., Zhou, B., Gage, F. H., Lehner, T., Senthil, G., Walsh, C. A., Chess, A., Courchesne, E., Gleeson, J. G., Kidd, J. M., Park, P. J., Pevsner, J., Vaccarino, F. M. 2017; 356 (6336): 395-?

    Abstract

    Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders.

    View details for DOI 10.1126/science.aal1641

    View details for Web of Science ID 000400143000042

    View details for PubMedID 28450582

  • Building a lineage from single cells: genetic techniques for cell lineage tracking NATURE REVIEWS GENETICS Woodworth, M. B., Girskis, K. M., Walsh, C. A. 2017; 18 (4): 230?44

    Abstract

    Resolving lineage relationships between cells in an organism is a fundamental interest of developmental biology. Furthermore, investigating lineage can drive understanding of pathological states, including cancer, as well as understanding of developmental pathways that are amenable to manipulation by directed differentiation. Although lineage tracking through the injection of retroviral libraries has long been the state of the art, a recent explosion of methodological advances in exogenous labelling and single-cell sequencing have enabled lineage tracking at larger scales, in more detail, and in a wider range of species than was previously considered possible. In this Review, we discuss these techniques for cell lineage tracking, with attention both to those that trace lineage forwards from experimental labelling, and those that trace backwards across the life history of an organism.

    View details for DOI 10.1038/nrg.2016.159

    View details for Web of Science ID 000396338700008

    View details for PubMedID 28111472

    View details for PubMedCentralID PMC5459401

  • Strict in vivo specificity of the Bcl11a erythroid enhancer BLOOD Smith, E. C., Luc, S., Croney, D. M., Woodworth, M. B., Greig, L. C., Fujiwara, Y., Minh Nguyen, Sher, F., Macklis, J. D., Bauer, D. E., Orkin, S. H. 2016; 128 (19): 2338?42

    Abstract

    BCL11A, a repressor of human fetal (?-)globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such, this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10-kb intronic sequences were removed. Bcl11a enhancer-deleted mice, Bcl11a(?enh), phenocopy the BCL11A-null state with respect to alterations of globin expression, yet are viable and exhibit no observable blood, brain, or other abnormalities. These preclinical findings provide strong in vivo support for genetic modification of the enhancer for therapy of hemoglobin disorders.

    View details for DOI 10.1182/blood-2016-08-736249

    View details for Web of Science ID 000388100700010

    View details for PubMedID 27707736

    View details for PubMedCentralID PMC5106112

  • Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers CELL REPORTS Woodworth, M. B., Greig, L. C., Liu, K. X., Ippolito, G. C., Tucker, H. O., Macklis, J. D. 2016; 15 (5): 999-1012

    Abstract

    The 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.

    View details for DOI 10.1016/j.celrep.2016.03.064

    View details for Web of Science ID 000376164600011

    View details for PubMedID 27117402

    View details for PubMedCentralID PMC4873759

  • Ctip1 Controls Acquisition of Sensory Area Identity and Establishment of Sensory Input Fields in the Developing Neocortex NEURON Greig, L. C., Woodworth, M. B., Greppi, C., Macklis, J. D. 2016; 90 (2): 261-277

    Abstract

    While 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 programs of gene expression, 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.

    View details for DOI 10.1016/j.neuron.2016.03.008

    View details for Web of Science ID 000374504400009

    View details for PubMedID 27100196

    View details for PubMedCentralID PMC4873772

  • Somatic mutation in single human neurons tracks developmental and transcriptional history SCIENCE Lodato, M. A., Woodworth, M. B., Lee, S., Evrony, G. D., Mehta, B. K., Karger, A., Lee, S., Chittenden, T. W., D'Gama, A. M., Cai, X., Luquette, L. J., Lee, E., Park, P. J., Walsh, C. A. 2015; 350 (6256): 94?98

    Abstract

    Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function.

    View details for DOI 10.1126/science.aab1785

    View details for Web of Science ID 000362098300053

    View details for PubMedID 26430121

    View details for PubMedCentralID PMC4664477

  • Katanin p80 Regulates Human Cortical Development by Limiting Centriole and Cilia Number NEURON Hu, W. F., Pomp, O., Ben-Omran, T., Kodani, A., Henke, K., Mochida, G. H., Yu, T. W., Woodworth, M. B., Bonnard, C., Raj, G., Tan, T., Hamamy, H., Masri, A., Shboul, M., Al Saffar, M., Partlow, J. N., Al-Dosari, M., Alazami, A., Alowain, M., Alkuraya, F. S., Reiter, J. F., Harris, M. P., Reversade, B., Walsh, C. A. 2014; 84 (6): 1240?57

    Abstract

    Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.

    View details for DOI 10.1016/j.neuron.2014.12.017

    View details for Web of Science ID 000346574500016

    View details for PubMedID 25521379

    View details for PubMedCentralID PMC4485387

  • Molecular logic of neocortical projection neuron specification, development and diversity NATURE REVIEWS NEUROSCIENCE Greig, L. C., Woodworth, M. B., Galazo, M. J., Padmanabhan, H., Macklis, J. D. 2013; 14 (11): 755-769

    Abstract

    The 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.

    View details for DOI 10.1038/nrn3586

    View details for Web of Science ID 000325918900008

    View details for PubMedID 24105342

    View details for PubMedCentralID PMC3876965

  • SnapShot: Cortical Development CELL Woodworth, M. B., Greig, L. C., Kriegstein, A. R., Macklis, J. D. 2012; 151 (4): 918-?

    View details for DOI 10.1016/j.cell.2012.10.004

    View details for Web of Science ID 000310921200023

    View details for PubMedID 23141546

    View details for PubMedCentralID PMC3694327

  • Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. The Journal of neuroscience : the official journal of the Society for Neuroscience Hung, A. Y., Futai, K., Sala, C., Valtschanoff, J. G., Ryu, J., Woodworth, M. A., Kidd, F. L., Sung, C. C., Miyakawa, T., Bear, M. F., Weinberg, R. J., Sheng, M. 2008; 28 (7): 1697?1708

    Abstract

    Experience-dependent changes in the structure of dendritic spines may contribute to learning and memory. Encoded by three genes, the Shank family of postsynaptic scaffold proteins are abundant and enriched in the postsynaptic density (PSD) of central excitatory synapses. When expressed in cultured hippocampal neurons, Shank promotes the maturation and enlargement of dendritic spines. Recently, Shank3 has been genetically implicated in human autism, suggesting an important role for Shank proteins in normal cognitive development. Here, we report the phenotype of Shank1 knock-out mice. Shank1 mutants showed altered PSD protein composition; reduced size of dendritic spines; smaller, thinner PSDs; and weaker basal synaptic transmission. Standard measures of synaptic plasticity were normal. Behaviorally, they had increased anxiety-related behavior and impaired contextual fear memory. Remarkably, Shank1-deficient mice displayed enhanced performance in a spatial learning task; however, their long-term memory retention in this task was impaired. These results affirm the importance of Shank1 for synapse structure and function in vivo, and they highlight a differential role for Shank1 in specific cognitive processes, a feature that may be relevant to human autism spectrum disorders.

    View details for DOI 10.1523/JNEUROSCI.3032-07.2008

    View details for PubMedID 18272690

    View details for PubMedCentralID PMC2633411

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