Undergraduate degree, Carleton College in Minnesota
PhD, Molecular Biology, UC Berkeley
Postdoctoral fellow, Vanderbilt University and the Center for Neurobiology at Columbia University
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
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.
Awards and Honors
- Pew Scholar
- Basil O'Connor Award
- McKnight Scholar
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
- "Magical state" of embryonic stem cells may help overcome hurdles to therapeutics, 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, May 27, 2008
- Sharing the road, April 10, 2008
- A mutation named Magellan steers nerve cells off course, November 21, 2007
- Salk neurobiologist receives Javits Neuroscience Investigator Award, August 24, 2007
- Detailed 3-D image catches a key regulator of neural stem cell differentiation in action, December 7, 2006
- New roles for growth factors: Enticing nerve cells to muscles, June 20, 2006
- In mice, walking (and running) depends on nerve cell chatter during development, April 13, 2005
- Molecular 'zipcode' guides nerves to correct places in body, April 7, 2005
- Motor Nerve Cell "Factory" Findings May Elicit Treatments for Spinal Cord Injury, Disease, June 4, 2003
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