Clinical Focus

  • Fellow
  • Neuroimmunology

Lab Affiliations

All Publications

  • Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis. Nature neuroscience Mader, M. M., Napole, A., Wu, D., Atkins, M., Scavetti, A., Shibuya, Y., Foltz, A., Hahn, O., Yoo, Y., Danziger, R., Tan, C., Wyss-Coray, T., Steinman, L., Wernig, M. 2024


    Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) shows promising benefits for relapsing-remitting MS in open-label clinical studies, but the cellular mechanisms underlying its therapeutic effects remain unclear. Using single-nucleus RNA sequencing, we identify a reactive myeloid cell state in chronic experimental autoimmune encephalitis (EAE) associated with neuroprotection and immune suppression. HCT in EAE mice results in an increase of the neuroprotective myeloid state, improvement of neurological deficits, reduced number of demyelinated lesions, decreased number of effector Tcells and amelioration of reactive astrogliosis. Enhancing myeloid cell incorporation after a modified HCT further improved these neuroprotective effects. These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the CNS.

    View details for DOI 10.1038/s41593-024-01609-3

    View details for PubMedID 38514857

  • ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yang, R., Walder-Christensen, K. K., Kim, N., Wu, D., Lorenzo, D. N., Badea, A., Jiang, Y., Yin, H. H., Wetsel, W. C., Bennett, V. 2019; 116 (30): 15262-15271


    Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of ANK2, a high-confidence autism spectrum disorder (ASD) gene. We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches. Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function. Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations.

    View details for DOI 10.1073/pnas.1904348116

    View details for Web of Science ID 000476715500071

    View details for PubMedID 31285321

    View details for PubMedCentralID PMC6660793

  • Rbm8a Haploinsufficiency Disrupts Embryonic Cortical Development Resulting in Microcephaly JOURNAL OF NEUROSCIENCE Mao, H., Pilaz, L., McMahon, J. J., Golzio, C., Wu, D., Shi, L., Katsanis, N., Silver, D. L. 2015; 35 (18): 7003-7018


    The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of the 1q21.1 locus has been implicated in the etiology of neurodevelopmental phenotypes; however, the role of 1q21.1 genes in neurogenesis has remained elusive. Here, we show that haploinsufficiency for Rbm8a, an exon junction complex (EJC) component within 1q21.1, causes severe microcephaly and defective neurogenesis in the mouse. At the onset of neurogenesis, Rbm8a regulates radial glia proliferation and prevents premature neuronal differentiation. Reduced Rbm8a levels result in subsequent apoptosis of neurons, and to a lesser extent, radial glia. Hence, compared to control, Rbm8a-haploinsufficient brains have fewer progenitors and neurons, resulting in defective cortical lamination. To determine whether reciprocal dosage change of Rbm8a alters embryonic neurogenesis, we overexpressed human RBM8A in two animal models. Using in utero electroporation of mouse neocortices as well as zebrafish models, we find RBM8A overexpression does not significantly perturb progenitor number or head size. Our findings demonstrate that Rbm8a is an essential neurogenesis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8A may contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions.

    View details for DOI 10.1523/JNEUROSCI.0018-15.2015

    View details for Web of Science ID 000356668400004

    View details for PubMedID 25948253

    View details for PubMedCentralID PMC4420776