Scott H. Soderling, Ph.D. (University of Washington)
Associate Professor, Cell Biology
Associate Professor, Neurobiology
Co-Director, BAC Recombineering Facility
318 Nanaline Duke Building, Box 3709
Duke University Medical Center
Durham, NC 27710
Telephone (919) 684-9001
Fax (919) 684-5481
The capacity of the 100 billion neurons in the human brain to function within neuronal circuits underlies all human behaviors, thoughts, emotions and memories. Precise control of the migration of neural progenitors and the development of trillions of synapses is critical for accurate neuronal network formation and normal brain function. Defects in these developmental programs are associated with congenital neurological disorders such as intellectual disability, autism, and schizophrenia. Because CNS function depends on proper neuronal migration and complex synaptic connections, it is a highly tractable model system to analyze Rho-family GTPase signaling to the cytoskeleton that is directly relevant to human health. Our laboratory studies how actin signaling pathways are organized and how their disruption in mice can model multiple neurologic disorders, including intellectual disability, schizophrenia, and autism spectrum disorders.
Spatial Regulation of Rho GTPase Signaling: Rho-family GTPases (typified by Rho, Rac, and Cdc42) function as intracellular switches which, among other functions, rapidly activate actin polymerization and reorganization in vivo. Almost one percent of human proteins have been identified as either regulators or effectors for the 22 different Rho-family GTPases. Consistent with this widespread influence Rho-family GTPases regulate diverse cellular functions. These include polarization, adhesion, intracellular trafficking, migration, and neuronal synapse formation and plasticity. Perhaps the most remarkable feature of the Rho-family GTPases is their ability to interact with many different regulators and effectors. For example, Rac activity can be regulated by several different GEFs (activators) or GAPs (inactivators), many of which are co-expressed in the same cell. Furthermore, once activated, Rac can bind to and modulate the activity of an even larger number of different downstream effectors. The large excess of regulators and effectors when compared to Rho-family GTPases means that individual GTPases do not function as simple binary switches. Rather, they behave as signaling multiplexers that can pair a given upstream cue with a specific cellular effector. How does a GTPase achieve this when faced with such a large diversity of potential interactions? We have focused on signaling complexes organized around Rho-family GAPs and, using novel proteomic approaches, we have discovered how many of these complexes are regulated by protein interactions and phosphorylation. Current work is determining how these interactions are relevant to important disorders such as intellectual disability and hydrocephalus. Additionally, we are working on re-engineering the activity of these pathways using light-regulated domains to determine how they influence subcellular specializations in neurons such as dendritic spines.
Regulation of dendritic spines- roles in neuropsychiatric and developmental disorders: Dendritic spines are small protrusions (less than one femtoliter in volume) that serve as postsynaptic specializations for the majority of excitatory synapses in the central nervous system. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Mutations in pathways that regulate synaptic actin in humans and mice are associated with neurological disorders (humans) and related endophenotypes (mice). Thus, understanding the signals that instruct spine development and function is crucial to the understanding of synaptic mechanisms believed to underlie complex behaviors and disease. We study a signaling pathway that is the main mechanism driving de novo branched actin assembly in spines through the activation of WAVE1 and Arp2/3 downstream of Rac and SrGAP3 regulation. Current work is focused on how this pathway influences the emergence of Schizophrenia, Autism, and Fragile-X syndrome-related phenotypes. These multidisciplinary projects combine mouse genetic models, live imaging analysis of synapses in tissue, electrophysiology, and behavioral analysis.
Hazai D, Szudoczki R, Ding J, Soderling SH, Weinberg RJ, Sotonyi P, Racz B. Ultrastructural abnormalities in CA1 hippocampus caused by deletion of the actin regulator WAVE-1. PLoS One. 2013;8(9):e75248.
Zhou k, Muroyama A, Underwood J, Leylek R, Ray S, Soderling SH, Lechler T. Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation. Proc Natl Acad Sci U S A. 2013 Sept 16. PMID: 24043783
Kim IH, Racz B, Wang H, Burianek L, Weinberg R, Yasuda R, Wetsel WC, Soderling SH. Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities. J Neurosci. 2013 Apr 3;33(14):6081-6092.
Burianek LE, Soderling SH. Under lock and key: Spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes. Semin Cell Dev Biol. 2013 Jan 3. pii: S1084-9521(12)00229-7.
Uezu A, Okada H, Murakoshi H, Del Vescovo CD, Yasuda R, Diviani D, Soderling SH. Modified SH2 domain to phototrap and identify phosphotyrosine proteins from subcellular sites within cells. Proc Natl Acad Sci U S A. 2012 Oct 1. [Epub ahead of print] PMID: 23027962 [PubMed - as supplied by publisher] Related citations
Kim IH, Carlson BR, Heindel CC, Kim H, Soderling SH. Disruption of wave associated Rac-GAP (Wrp) leads to abnormal adult neural progenitor migration associated with hydrocephalus. J Biol Chem. 2012 Sep 24. [Epub ahead of print] PMID: 23007397 [PubMed - as supplied by publisher] Related citations
Okada H, Uezu A, Soderblom EJ, Moseley MA 3rd, Gertler FB, Soderling SH. Peptide array X-linking (PAX): a new peptide-protein identification approach. PLoS One. 2012;7(5):e37035. Epub 2012 May 14. PMID: 22606326 [PubMed - in process] Related citations
Okada, H., Uezu, A., Mason, F.M., Soderblom, E.J., Moseley III, M.A., Soderling, S.H. (2011) SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes. Sci Signal, 4(201):rs13.
Mason, F.M., Heimsath, E.G., Higgs, H.N., and Soderling, S.H. (2011) Bi-modal regulation of a formin by srGAP2. J Biol Chem, 286(8):6577-6586.
Carlson, B.R., Lloyd, K.E., Kruszewski, A., Rodriguiz, R.M., Faytell, M., Wetsel, W.C., and Soderling, S.H. (2011) WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory. J Neurosci, 31(7):2447-2460.