Gene Expression Laboratory
Howard Hughes Medical Institute Investigator
Benjamin H. Lewis Chair
The main objective of Samuel Pfaff, a professor in the Gene Expression Laboratory, is to discover how nerve cells are formed and wire up correctly, focusing on the fetal development of the spinal cord.
Of special interest to him is how motor neurons develop and make connections between the spinal cord and muscles in the body, since these connections are necessary for all body movements. Spinal cord injuries lead to paralysis because motor neuron function is disrupted. Degenerative diseases such as ALS (Lou Gehrig's disease), spinal muscle atrophy and post-polio syndrome result from the loss of motor neurons.
"Our brains are composed of neuronal circuits with an estimated 100 trillion connections. My lab is interested in unmasking the strategies that nature has devised to generate this immense diversity of cells and complexity of connections by focusing on the way that the spinal cord is assembled during fetal development. We expect this information to provide novel insight into how we can harness 'embryonic pathways' to repair or augment the central nervous system to treat birth defects, injuries, diseases and aging."
The neuromuscular circuitry that controls bodily movements relies on constant sensory feedback to fine-tune its commands to hundreds of muscles. Muscle fibers are each controlled by one motor neuron in the spinal cord that relays signals from the brain. Sensory receptors send information from the periphery back to the central nervous system. These nerves are not unlike a roadway, with orderly traffic moving in both directions.
The traditional view has been that during embryonic development, sensory and motor neurons are able to incorporate into tightly coordinated pathways without getting mixed up because growth cones—structures that guide growing axons to their destination—are studded with Eph proteins that constantly search their environments for other proteins called ephrins, which nudge them in the right direction. (Axons are long projections that conduct electrical impulses away from the nerve cell body.) Researchers in Pfaff's laboratory, however, found that neurons not only carry both types of proteins, but that the role of Ephs and ephrins can change, raising the question of what happens when adjacent neurons bump into one another.
To find the answer, Pfaff's team studied sensory and motor neurons, which extend their axons along the same pathway to the periphery. They found that with ephrin/Eph signaling intact, the axons sorted into separate fascicles containing either sensory or motor axons, but never both. When they deleted EphA3 and EphA4 in motor neurons, however, sorting between the fascicles of the motor and sensory axons broke down; instead of reaching for muscles, some motor neurons made a U-turn, joined the sensory lane and headed back toward the spinal cord.
Ephrins and Ephs appear to control where the axons grow, as well as maintain the normal arrangement between the motor and sensory pathways. They also play a major role in preventing spinal cord neurons from regenerating after injuries. As scientists in the spinal cord field work to overcome the block preventing axonal growth within the central nervous system, Pfaff's findings demonstrate that this research needs to be approached cautiously, lest it promote indiscriminate motor axon growth and cause severe problems.
Left to right:
Gráinne "G" Whitman, Wes Gifford, Annie Chivatakarn, Neal Amin, Matt Pankratz, Ge Bai, Ariel Levine, Kathryn Lewallen, Shawn Driscoll, Sam Pfaff, Will Alaynick, Chris Hinckley, Dario Bonanomi, Matt Sternfeld, Laura Franco, Karen Lettieri, Tiffany Poon, Marito Hayashi, Todd Macfarlan
Hester, M.E., Murtha, M.J., Song, SW., Rao, M. Miranda, C.J., Meyer, K., Tian, J., Boulting, G., Schaffer, D.V., Zhu, M.X., Pfaff, S.L., Gage, F.H., Kaspar, B.K. (2011). Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Molecular Therapy (In Press).
Bruno I.G., Karam, R., Huang, L., Bhardwaj, A., Lou, C.H., Shum, E.Y., Song, H.W., Corbett, M.A., Gifford, W.D., Gecz, J., Pfaff, S.L., Wilkinson, M.F. (2011). Identification of a MicroRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol Cell. May 20;42(4):500-510. PMID: 21596314 [PubMed - in process].
Liang, X., Song, M.R., Xu, Z., Lanuza, G.M., Liu, Y., Zhuang, T., Chen, Y., Pfaff, S.L., Evans, S.M., Sun, Y. (2011). Isl1 Is required for multiple aspects of motor neuron development. Mol Cell Neurosci. May 4. (electronically available, printed article in press, PMCID not able to be assigned at this time).
Macfarlan, T.S., Gifford, W.D., Agarwal, S., Driscoll, S., Lettieri, S., Wang, J., Andrews, S.E., Franco, F., Rosenfeld, M.G., Ren, B., and Pfaff, S.L. (2011). Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes and Dev 25:594-607. PMID:21357675.
Bai, G., Chivatakarn, O., Bonanomi, D., Lettieri, K., Franco, L., Xia, C., Stein, E., Ma, L., Lewcock, J.W., Pfaff, S.L. (2011). Presenilin-dependent receptor processing is required for axon guidance. Cell/144(1):106-118. (PMC3034090) PMID:21215373
Qu Y., Glasco D.M., Zhou, L., Sawant, A., Ravni, A., Fritzsch, B., Damrau, C., Murdoch, J.N., Evans, S., Pfaff, S.L., Formstone, C., Goffinet, A.M., Chandrasekhar, A., and Tissir, F. (2010). Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice. J. Neurosci. 30:9392-401. PMID 20631168.
Meyer, A., Gallarda, B.W., Pfaff, S.L., and Alaynick, W.A. (2010). Spinal cord electrophysiology. J. Vis. Exp. 35: Pii.1660. doi:10.3791/1660.
Zhang, M., Liu, J., Kim, Y., Dixon, J.E., Pfaff, S.L., Gill, G.N., Noel, J.P., and Zhang, Y. (2010). Structural and functional analysis of the phosphoryl transfer reaction mediated by the human small C-terminal domain phosphatase, Scp1. Protein Sci. 19:974-86. PMID: 20222012.
Song, M.R., Sun, Y, Bryson, A., Gill, G.N., Evans, S.M., and Pfaff, S.L. (2009). Islet-to-LMO stoichiometries control the function of transcription complexes that specify motor neuron and V2a interneuron identity. Development 136(17): 2923-32. PMID: 19666821.
Pfaff, S.L. (2008). Developmental neuroscience: Hox and Fox. Nature 7211: 295-7. PMID: 18800121.
Pankratz, M.T. and Pfaff, S.L. (2008). Signaling pathways that regulate cell fate in the embryonic spinal cord. Handbook of Cell Signaling.
Song, M.R. and Pfaff, S.L. (2008) Motor neuron specification in vertebrates. In: Encyclopedia of Neuroscience. L. Squire, T. Albright, F. Bloom, F. Gage & N. Spitzer, Eds., Academic Press, Oxford
Macfarlan, T. and Pfaff, S.L. (2008) Transcriptional networks regulating cell specification within the spinal cord. In: Encyclopedia of Neuroscience. L. Squire, T. Albright, F. Bloom, F. Gage & N. Spitzer, Eds., Academic Press, Oxford
Cao, X., Pfaff, S.L., and Gage, F.H. (2008). YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev. 23: 3320-34. PMID: 19015275.
Lee, S., Lee, B., Joshi, K., Pfaff, S.L., Lee, J.W., and Lee, S.-K. (2008). A regulatory network to segregate the identity of neuronal subtypes. Dev. Cell 6: 877-89. PMID: 18539116.
Ma, Y.C., Song, M.R., Park, J.P., Henry Ho, H.Y., Hu, L., Kurtev, M.V., Zieg, J., Ma, Q., Pfaff, S.L., and Greenberg, M.E. (2008). Regulation of motor neuron specification by phosphorylation of neurogenin 2. Neuron 58: 65-77. PMID: 18400164.
Gallarda, B.W., Bonanomi, D., Muller, D., Brown, A., Alaynick, W.A., Andrews, S.E., Lemke, G., Pfaff, S.L., and Marquardt, T. (2008). Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science 320: 233-236. PMID: 18403711.
Ghosh, S., Marquardt, T., Thaler, J. P., Carter, N., Andrews, S. E., Pfaff, S. L., and Hunter, T. (2008). Instructive role of aPKCzeta subcellular localization in the assembly of adherens junctions in neural progenitors. Proc Natl Acad Sci U S A 105, 335-340.
Lewcock, J. W., Genoud, N., Lettieri, K., and Pfaff, S. L. (2007). The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics. Neuron 56, 604-620.
Fox, M.A., Sanes, J.R., Borza, D.B., Eswarakumar, V.P., Fassler, R., Hudson, B.G., John, S.W., Ninomiya, Y., Pedchenko, V., Pfaff, S.L., Rheault, M.N., Sado, Y., Segal, Y., Werle, M.J., and Umemori, H. (2007). Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell 129: 179-93.
Peng, C.Y., Yajima, H., Burns, C.E., Zon, L.I., Sisodia, S.S., Pfaff, S.L., and Sharma, K. (2007). Notch and MAML signaling drives Scl-dependent interneuron diversity in the spinal cord. Neuron 53: 813-27.
Cao, X., Pfaff, S.L., and Gage, F.H. (2007). A functional study of miR-124 in the developing neural tube. Genes and Dev. 21: 531-6.
Odani, N., Pfaff, S.L., Nakamura, H., and Funahashi, J. (2007). Cloning and developmental expression of a chick G-protein-coupled receptor SCGPR1. Gene Expr. Patterns 7: 375-80.
Kashani, A. H., Qiu, Z., Jurata, L., Lee, S. K., Pfaff, S., Goebbels, S., Nave, K. A., and Ghosh, A. (2006). Calcium activation of the LMO4 transcription complex and its role in the patterning of thalamocortical connections. J Neurosci 26, 8398-8408.
Zhang, Y., Kim, Y., Genoud, N., Gao, J., Kelly, J.W., Pfaff, S.L., Gill, G.N., Dixon, J.E., and Noel, J.P. (2006). Determinants for dephosphorylation of the RNA polymerase II C-terminal domain by Scp1. Mol. Cell 24: 759-70.
Shirasaki R., Lewcock J.W., Lettieri K., Pfaff S.L. FGF as a target-derived chemoattractant for developing motor axons genetically programmed by the LIM code. Neuron. 2006 Jun 15;50(6):841-53.
Song M.R., and Pfaff S.L. (2005). Hox genes: the instructors working at motor pools. Cell 123: 363-5.
Myers C.P., Lewcock J.W., Hanson M.G., Gosgnach S., Aimone J.B., Gage F.H., Lee K.F., Landmesser L.T., Pfaff S.L. Cholinergic input is required during embryonic development to mediate proper assembly of spinal locomotor circuits. Neuron. 2005 Apr 7;46(1):37-49.
Marquardt T., Shirasaki R., Ghosh S., Andrews S.E., Carter N., Hunter T., Pfaff S.L. Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell. 2005 Apr 8;121(1):127-39.
Yeo M., Lee S.K., Lee B., Ruiz E.C., Pfaff S.L., Gill G.N. Small CTD phosphatases function in silencing neuronal gene expression. Science. 2005 Jan 28;307(5709):596-600.
Thaler J.P., Koo S.J., Kania A., Lettieri K., Andrews S., Cox C., Jessell T.M., Pfaff S.L. A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron. 2004 Feb 5;41(3):337-50.
Lee S-K., Pfaff S.L. Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors. Neuron. 2003 Jun 5;38(5):731-45.
Thaler, J.P., Lee, S-K., Jurata, L.W., Gill, G.N., Pfaff, S.L. (2002). LIM Factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell 110: 237-249.
Sharma, K., Leonard, A.E., Lettieri, K., and Pfaff, S.L. (2000). Genetic and epigenetic mechanisms contribute to motor neuron pathfinding. Nature 406: 515-519.
Brown, A., Yates, P.A., Burrola, P., Ortu-o, D., Vaidya, A., Jessell, T.M., Pfaff, S.L., O'Leary, D.D.M., and Lemke, G. (2000). Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102:77-88.
Salk News Releases
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June 13, 2012
Complex wiring of the nervous system may rely on just a handful of genes and proteins
February 10, 2012
Unlocking the secret(ase) of building neural circuits
January 18, 2011
Salk Institute scientist receives $15.6 million CIRM Disease Team Award to develop novel stem-cell derived therapy for Lou Gehrig's Disease
October 28, 2009
Salk scientists selected as Howard Hughes Medical Institute investigators
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Sharing the road
April 10, 2008
A mutation named Magellan steers nerve cells off course
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Salk neurobiologist receives Javits Neuroscience Investigator Award
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Detailed 3-D image catches a key regulator of neural stem cell differentiation in action
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June 20, 2006
In mice, walking (and running) depends on nerve cell chatter during development
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Molecular 'zipcode' guides nerves to correct places in body
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Motor Nerve Cell "Factory" Findings May Elicit Treatments for Spinal Cord Injury, Disease
June 4, 2003
Awards and Honors
- Pew Scholar
- Basil O'Connor Award
- McKnight Scholar