Scott H. Soderling, Ph.D. (University of Washington)
Associate Professor, Department of Cell Biology
Associate Professor, Department of Neurobiology
Director, Transgenic Mouse Facility
Director of Graduate Studies, Cell Biology
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.
Yan Z, Kim E, Datta D, Lewis DA, Soderling SH. (2016) Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders? J Neurosci. 36(45):11411-11417.
Spence EF, Kanak DJ, Carlson BR, Soderling SH. (2016) The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing. J Neurosci. 14;36(37):9696-709.
Uezu A, Kanak DJ, Bradshaw TW, Soderblom EJ, Catavero CM, Burette AC, Weinberg RJ, Soderling SH. (2016) Identification of an elaborate complex mediating postsynaptic inhibition. Science. 9;353(6304):1123-9.
Rossi MA, Li HE, Lu D, Kim IH, Bartholomew RA, Gaidis E, Barter JW, Kim N, Cai MT, Soderling SH, Yin HH (2016) A GABAergic nigrotectal pathway for coordination of drinking behavior. Nat Neurosci 19(5):742-8.
Singh SK, Stogsdill JA, Pulimood NS, Dingsdale H, Kim YH, Pilaz LJ, Kim IH, Manhaes AC, Rodrigues WS Jr., Pamukcu A, Enustun E, Ertuz Z, Scheiffle P, Soderling SH, Silver DL, Ji RR, Medina AE, Eroglu C (2016) Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin. Cell 164(1-2):183-96.
Spence EF, Soderling SH (2015) Actin Out: Regulation of the Synaptic Cytoskeleton. J Biol Chem. 290(48):28613-22.
Zuchero JB, Fu MM, Sloan SA, Ibrahim A, Olson A, Zaremba A, Dugas JC, Wienbar S, Caprariello AV, Kantor C, Leonoudakus D, Lariosa-Willingham K, Kronenberg G, Gertz K, Soderling SH, Miller RH, Barres BA. (2015) CNS Myelin Wrapping Is Driven by Actin Disassembly. Dev Cell. 34(2):152-67.
Kim IH, Rossi MA, Aryal DK, Racz B, Kim N, Uezu A, Wang F, Wetsel WC, Weinberg RJ, Yin H, Soderling SH. (2015) Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine. Nat Neurosci. 18(6):883-91.
Risher W.C., Patel S., Kim I.H., Uezu A., Bhagat S., Wilton D.K., Pilaz L.J., Singh Alvarado J., Calhan O.Y., Silver D.L., Stevens B., Calakos N., Soderling S.H., Eroglu C. (2014) Astrocytes refine cortical connectivity at dendritic spines. Elife 17;3
Kim IH, Wang H, Soderling SH, Yasuda R. (2014) Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall. Elife. 8;3