Paul Forscher, PhD
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Research Summary
Have you ever wondered how your brain got wired? How a single neuron finds a unique signaling partner among over 10 billion other neurons? During
development neurons not only face this daunting task but often migrate extremely long distances (>50,000 cell diameter equivalents) to accomplish it.
My lab focuses on this problem and the specialized guidance device called the growth cone that provides the motility and signal transduction capabilities
needed for axon guidance. Current lab projects include: 1) Molecular motor and cytoskeletal protein dynamics underlying growth cone motility. 2) Cell surface receptors involved in target recognition. 3) Investigation of signal transduction pathways involved in controlling the cytoskeletal protein effectors involved. We address the relevant cell biological processes using a "molecular physiology"
approach. This typically entails generation of molecular probes to investigate dynamics of the process and/or protein-protein interactions in living neurons. We use a variety of high resolution imaging and biophysical approaches such as: multimode fluorescent speckle microscopy, laser trapping, photobleaching, and "caged" probe photoactivation.
Extensive Research Description
- Actin filament turnover dynamics in neuronal growth
- Rho GTPase and Ca signaling crosstalk in regulation of motility
- Mechano-transduction in axon growth and neuronal differentiation
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Selected Publications
- Regulation of axon growth by myosin II–dependent mechanocatalysis of cofilin activityZhang XF, Ajeti V, Tsai N, Fereydooni A, Burns W, Murrell M, De La Cruz EM, Forscher P. Regulation of axon growth by myosin II–dependent mechanocatalysis of cofilin activity. Journal Of Cell Biology 2019, 218: 2329-2349. PMID: 31123185, PMCID: PMC6605792, DOI: 10.1083/jcb.201810054.
- Local Arp2/3-dependent actin assembly modulates applied traction force during apCAM adhesion site maturationBuck KB, Schaefer AW, Schoonderwoert VT, Creamer MS, Dufresne ER, Forscher P. Local Arp2/3-dependent actin assembly modulates applied traction force during apCAM adhesion site maturation. Molecular Biology Of The Cell 2016, 28: 98-110. PMID: 27852899, PMCID: PMC5221634, DOI: 10.1091/mbc.e16-04-0228.
- Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel GatingZhang Y, Zhang XF, Fleming MR, Amiri A, El-Hassar L, Surguchev AA, Hyland C, Jenkins DP, Desai R, Brown MR, Gazula VR, Waters MF, Large CH, Horvath TL, Navaratnam D, Vaccarino FM, Forscher P, Kaczmarek LK. Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating. Cell 2016, 165: 434-448. PMID: 26997484, PMCID: PMC4826296, DOI: 10.1016/j.cell.2016.02.009.
- Erratum: CORRIGENDUM: Regeneration of Aplysia Bag Cell Neurons is Synergistically Enhanced by Substrate-Bound Hemolymph Proteins and LamininHyland C, Dufresne E, Forscher P. Erratum: CORRIGENDUM: Regeneration of Aplysia Bag Cell Neurons is Synergistically Enhanced by Substrate-Bound Hemolymph Proteins and Laminin. Scientific Reports 2014, 4: 5582. PMCID: PMC4087918, DOI: 10.1038/srep05582.
- Dynamic peripheral traction forces balance stable neurite tension in regenerating Aplysia bag cell neuronsHyland C, Mertz AF, Forscher P, Dufresne E. Dynamic peripheral traction forces balance stable neurite tension in regenerating Aplysia bag cell neurons. Scientific Reports 2014, 4: 4961. PMID: 24825441, PMCID: PMC4019958, DOI: 10.1038/srep04961.
- Regeneration of Aplysia Bag Cell Neurons is Synergistically Enhanced by Substrate-Bound Hemolymph Proteins and LamininHyland C, Dufresne ER, Forscher P. Regeneration of Aplysia Bag Cell Neurons is Synergistically Enhanced by Substrate-Bound Hemolymph Proteins and Laminin. Scientific Reports 2014, 4: 4617. PMID: 24722588, PMCID: PMC3983596, DOI: 10.1038/srep04617.
- Elastic Coupling of Nascent apCAM Adhesions to Flowing Actin NetworksMejean CO, Schaefer AW, Buck KB, Kress H, Shundrovsky A, Merrill JW, Dufresne ER, Forscher P. Elastic Coupling of Nascent apCAM Adhesions to Flowing Actin Networks. PLOS ONE 2013, 8: e73389. PMID: 24039928, PMCID: PMC3765355, DOI: 10.1371/journal.pone.0073389.
- Protein kinase C activation decreases peripheral actin network density and increases central nonmuscle myosin II contractility in neuronal growth conesYang Q, Zhang XF, Van Goor D, Dunn AP, Hyland C, Medeiros N, Forscher P. Protein kinase C activation decreases peripheral actin network density and increases central nonmuscle myosin II contractility in neuronal growth cones. Molecular Biology Of The Cell 2013, 24: 3097-3114. PMID: 23966465, PMCID: PMC3784383, DOI: 10.1091/mbc.e13-05-0289.
- Calcineurin-dependent cofilin activation and increased retrograde actin flow drive 5-HT–dependent neurite outgrowth in Aplysia bag cell neuronsZhang XF, Hyland C, Van Goor D, Forscher P. Calcineurin-dependent cofilin activation and increased retrograde actin flow drive 5-HT–dependent neurite outgrowth in Aplysia bag cell neurons. Molecular Biology Of The Cell 2012, 23: 4833-4848. PMID: 23097492, PMCID: PMC3521690, DOI: 10.1091/mbc.e12-10-0715.
- Arp2/3 complex–dependent actin networks constrain myosin II function in driving retrograde actin flowYang Q, Zhang XF, Pollard TD, Forscher P. Arp2/3 complex–dependent actin networks constrain myosin II function in driving retrograde actin flow. Journal Of Cell Biology 2012, 197: 939-956. PMID: 22711700, PMCID: PMC3384413, DOI: 10.1083/jcb.201111052.
- Abstract 33: Implementing CAD cells quantify the relationships between Ig-CAM-mediated adhesion, force transduction, and actin dynamicsFuller M, Schaefer A, Mejean C, Forscher P. Abstract 33: Implementing CAD cells quantify the relationships between Ig-CAM-mediated adhesion, force transduction, and actin dynamics. Cancer Research 2012, 72: 33-33. DOI: 10.1158/1538-7445.am2012-33.
- Membrane Tension, Myosin Force, and Actin Turnover Maintain Actin Treadmill in the Nerve Growth ConeCraig EM, Van Goor D, Forscher P, Mogilner A. Membrane Tension, Myosin Force, and Actin Turnover Maintain Actin Treadmill in the Nerve Growth Cone. Biophysical Journal 2012, 102: 1503-1513. PMID: 22500750, PMCID: PMC3318135, DOI: 10.1016/j.bpj.2012.03.003.
- Model for Microtubule-Actin Interactions in Growth Cone MotilityCraig E, Schaefer A, Forscher P, Mogilner A. Model for Microtubule-Actin Interactions in Growth Cone Motility. Biophysical Journal 2010, 98: 364a. DOI: 10.1016/j.bpj.2009.12.1965.
- Coordination of Actin Filament and Microtubule Dynamics during Neurite OutgrowthSchaefer AW, Schoonderwoert VT, Ji L, Mederios N, Danuser G, Forscher P. Coordination of Actin Filament and Microtubule Dynamics during Neurite Outgrowth. Developmental Cell 2008, 15: 146-162. PMID: 18606148, PMCID: PMC2595147, DOI: 10.1016/j.devcel.2008.05.003.
- Myosin II Activity Facilitates Microtubule Bundling in the Neuronal Growth Cone NeckBurnette DT, Ji L, Schaefer AW, Medeiros NA, Danuser G, Forscher P. Myosin II Activity Facilitates Microtubule Bundling in the Neuronal Growth Cone Neck. Developmental Cell 2008, 15: 163-169. PMID: 18606149, PMCID: PMC2548298, DOI: 10.1016/j.devcel.2008.05.016.
- Filopodial actin bundles are not necessary for microtubule advance into the peripheral domain of Aplysia neuronal growth conesBurnette DT, Schaefer AW, Ji L, Danuser G, Forscher P. Filopodial actin bundles are not necessary for microtubule advance into the peripheral domain of Aplysia neuronal growth cones. Nature Cell Biology 2007, 9: 1360-1369. PMID: 18026092, DOI: 10.1038/ncb1655.
- Myosin II functions in actin-bundle turnover in neuronal growth conesMedeiros NA, Burnette DT, Forscher P. Myosin II functions in actin-bundle turnover in neuronal growth cones. Nature Cell Biology 2006, 8: 216-226. PMID: 16501565, DOI: 10.1038/ncb1367.
- Transmission of growth cone traction force through apCAM–cytoskeletal linkages is regulated by Src family tyrosine kinase activitySuter D, Forscher P. Transmission of growth cone traction force through apCAM–cytoskeletal linkages is regulated by Src family tyrosine kinase activity. Journal Of Cell Biology 2001, 155: 427-438. PMID: 11673478, PMCID: PMC2150837, DOI: 10.1083/jcb.200107063.
- Protein Kinase C Activation Promotes Microtubule Advance in Neuronal Growth Cones by Increasing Average Microtubule Growth LifetimesKabir N, Schaefer A, Nakhost A, Sossin W, Forscher P. Protein Kinase C Activation Promotes Microtubule Advance in Neuronal Growth Cones by Increasing Average Microtubule Growth Lifetimes. Journal Of Cell Biology 2001, 152: 1033-1044. PMID: 11238458, PMCID: PMC2198821, DOI: 10.1083/jcb.152.5.1033.
- Substrate–cytoskeletal coupling as a mechanism for the regulation of growth cone motility and guidanceSuter D, Forscher P. Substrate–cytoskeletal coupling as a mechanism for the regulation of growth cone motility and guidance. Developmental Neurobiology 2000, 44: 97-113. PMID: 10934315, DOI: 10.1002/1097-4695(200008)44:2<97::aid-neu2>3.0.co;2-u.
- Localization of unconventional myosins V and VI in neuronal growth conesSuter D, Espindola F, Lin C, Forscher P, Mooseker M. Localization of unconventional myosins V and VI in neuronal growth cones. Developmental Neurobiology 2000, 42: 370-382. PMID: 10645976, DOI: 10.1002/(sici)1097-4695(20000215)42:3<370::aid-neu8>3.0.co;2-v.
- A diffusion barrier maintains distribution of membrane proteins in polarized neuronsWinckler B, Forscher P, Mellman I. A diffusion barrier maintains distribution of membrane proteins in polarized neurons. Nature 1999, 397: 698-701. PMID: 10067893, DOI: 10.1038/17806.
- Binding of Protein Kinase C Isoforms to Actin in AplysiaNakhost A, Forscher P, Sossin W. Binding of Protein Kinase C Isoforms to Actin in Aplysia. Journal Of Neurochemistry 1998, 71: 1221-1231. PMID: 9721748, DOI: 10.1046/j.1471-4159.1998.71031221.x.
- The Ig Superfamily Cell Adhesion Molecule, apCAM, Mediates Growth Cone Steering by Substrate–Cytoskeletal CouplingSuter D, Errante L, Belotserkovsky V, Forscher P. The Ig Superfamily Cell Adhesion Molecule, apCAM, Mediates Growth Cone Steering by Substrate–Cytoskeletal Coupling. Journal Of Cell Biology 1998, 141: 227-240. PMID: 9531561, PMCID: PMC2132711, DOI: 10.1083/jcb.141.1.227.
- An emerging link between cytoskeletal dynamics and cell adhesion molecules in growth cone guidanceSuter D, Forscher P. An emerging link between cytoskeletal dynamics and cell adhesion molecules in growth cone guidance. Current Opinion In Neurobiology 1998, 8: 106-116. PMID: 9568398, DOI: 10.1016/s0959-4388(98)80014-7.
- Growth cone advance is inversely proportional to retrograde F-actin flowLin C, Forscher P. Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron 1995, 14: 763-771. PMID: 7536426, DOI: 10.1016/0896-6273(95)90220-1.
- Cytoskeletal reorganization underlying growth cone motilityLin C, Thompson C, Forscher P. Cytoskeletal reorganization underlying growth cone motility. Current Opinion In Neurobiology 1995, 5: 112. DOI: 10.1016/0959-4388(95)80095-6.
- Cytoskeletal reorganization underlying growth cone motilityLin C, Thompson C, Forscher P. Cytoskeletal reorganization underlying growth cone motility. Current Opinion In Neurobiology 1994, 4: 640-647. PMID: 7849519, DOI: 10.1016/0959-4388(94)90004-3.
- Brain myosin-V is a two-headed unconventional myosin with motor activityCheney R, O'Shea M, Heuser J, Coelho M, Wolenski J, Espreafico E, Forscher P, Larson R, Mooseker M. Brain myosin-V is a two-headed unconventional myosin with motor activity. Cell 1993, 75: 13-23. PMID: 8402892, DOI: 10.1016/s0092-8674(05)80080-7.
- In vitro motilities of the unconventional myosins, brush border myosin‐I, and chick brain myosin‐V exhibit assay‐dependent differences in velocityWolenski J, Cheney R, Forscher P, Mooseker M. In vitro motilities of the unconventional myosins, brush border myosin‐I, and chick brain myosin‐V exhibit assay‐dependent differences in velocity. Journal Of Experimental Zoology 1993, 267: 33-39. PMID: 8376949, DOI: 10.1002/jez.1402670106.
- Novel form of growth cone motility involving site-directed actin filament assemblyForscher P, Lin C, Thompson C. Novel form of growth cone motility involving site-directed actin filament assembly. Nature 1992, 357: 515-518. PMID: 1608453, DOI: 10.1038/357515a0.
- Calcium and polyphosphoinositide control of cytoskeletal dynamicsForscher P. Calcium and polyphosphoinositide control of cytoskeletal dynamics. Trends In Neurosciences 1989, 12: 468-474. PMID: 2479150, DOI: 10.1016/0166-2236(89)90098-2.