BIOGRAPHICAL  SKETCH

NAME: Sanes, Joshua R.

POSITION TITLE: Professor of Molecular & Cellular Biology

EDUCATION/TRAINING

INSTITUTION AND LOCATION

DEGREE

FIELD OF STUDY

Yale College, New Haven, CT

B.A.

06/1970

Biochemistry/Psychology

Harvard Medical School, Boston, MA

Ph.D.

01/1976

Neurobiology

Harvard Medical School, Boston, MA

Postdoc

07/1977

Neurobiology

University of California, San Francisco, CA

Postdoc

09/1979

Neurobiology

A.  Personal  statement

My colleagues and I have worked for almost 40 years to understand how synapses form in the mammalian nervous system: how axons find appropriate synaptic partners and how, once formed, the pre- and postsynaptic elements differentiate. We began with histological and surgical approaches, then added new methods as they became available or applicable: immunochemistry, molecular biology, genetic engineering in mice, live imaging and, most recently, electrophysiology. We have also helped develop some of these methods, including use of retroviral vectors for tracing lineage and migration, and generation of mice for multicolor (“Brainbow”) labeling of neurons. For the past decade, our focus has been on the retina, an accessible system for elucidating mechanisms responsible for development and function of central circuitry.

We have also used insights from retinal development as a starting point to analyze related issues, including deleterious effects of age and injury. Most recently, we have used retina to implement methods for

comprehensive classification and transcriptomic analysis of all neuronal types. Specific contributions are summarized in Section D; here I cite reviews that discuss these efforts.

a.  Sanes JR, Lichtman JW: Induction, assembly, maturation and maintenance of a postsynapticapparatus. Nat. Rev. Neurosci. 2001; 2:791-805.

b.  Sanes JR and Zipursky SL. Design principles of insect and vertebrate visual systems. Neuron. 66:15- 36, 2010.

c.  Sanes JR and Masland RH. The types of retinal ganglion cells: current status and implications for neuronal classification. Annual Reviews of Neuroscience 2015; 38:221-46

d.  Zeng H and Sanes JR. Neuronal cell type classification: challenges, opportunities and the path forward. Nature Reviews Neuroscience, 2017; 18: 530–546.

B1. Positions:

1980-1985       Assistant Professor, Department of Physiology and Biophysics, Washington University School of Medicine, St. Louis, MO

1985-1986       Sabbatical, Laboratory of Francois Jacob, Institut Pasteur, Paris, France

1985-1989       Associate Professor of Neurobiology, Washington University School of Medicine, St. Louis, MO 1989-2004       Professor of Neurobiology, Washington University School of Medicine, St. Louis, MO

1993                Wiersma Visiting Professor of Neurobiology, California Institute of Technology 1999                Sabbatical with Chris Henderson, IBDM, U. Marseille, France

1998-2002        Director, Neuroscience Graduate Program, Washington University 1999-2004  Alumni Endowed Professor of Neurobiology, Washington University

2004-               Jeff Tarr Professor of Molecular & Cellular Biology, Harvard University, Cambridge, MA 2004-                        Paul J. Finnegan Director, Center for Brain Science,                 Harvard University, Cambridge, MA 2008                Visiting Fellow, Trinity College, University of Cambridge

2013-               Visiting Scientist, Biogen

B2. Scholarships, Honors and Service:

Yale National Scholar, l966; Scholar of the House, Yale, 1969-1970; Phi Beta Kappa, l970; Sigma Xi, 1974; Sloan Fellow, l980-l982; Established Investigator, American Heart Assn., l98l-1986; Member, Senator Jacob Javits Center of Excellence in Neuroscience, 1985-1990; Editorial Boards (current): Neuron, BMC Biology, BMC Neuroscience, Neuroscience Bulletin; Editorial Boards (previous): Cell, Curr. Opin. Neurobiology, Development, Dev. Biology, Dev. Dynamics (assoc. editor), F1000 (section head), Mol. Cell Neurosci., J. Cell Biology (monitoring editor), J. Comp. Neurology, J. Neurocytol, J. Neuroscience (reviewing editor), Neural Development (co-editor in chief), Physiological Reviews, PLoS; Francis McNaughton Lecturer, Montreal Neurological Inst., 1987; McKnight Neuroscience Development Award, 1988-1990; Member, NIH Study Section, 1988-1992; Javits Neuroscience Investigator (Merit) Awards, NIH, 1989-1995, 2005-2011, 2012; Councilor, Society for Neuroscience, 1990-1994; F.E. Bennett Lecturer, American Neurological Assn., 1991; Scientific Advisory Committee, Muscular Dystrophy Assn., 1991-2001; Fellow of the American Association for the Advancement of Science, 1992; Board of Scientific Counselors, NINDS, NIH, 1993-1998; Gordon Conference on Neural Development, co-chair, 1993, chair, 1995; Publications Committee, Society for Neuroscience, 1993-1998; Member, Dana Alliance, 1993-; Woolsey Lecturer, University of Wisconsin, 1996; Keynote speaker, Gordon Conference on Neural Plasticity, 1997; Kuffler Lecturer, Harvard Medical School, 1996; Neuroscience Advisory Committee, Klingenstein Fund, 1998-; Board of Scientific Overseers, Jackson Laboratory, 1998-2003; McKnight Senior Investigator Award, 1998; Richard Bunge Lecturer, University of Miami, 1998; National Advisory Council, NINDS, NIH, 1999-2003; Alden Spencer Award, Columbia University 2000; Keystone Symposium on Synapse Formation, co-chair, 2000; External Advisory Committee; Specialized Neuroscience Program, Meharry Medical College, chair, 2001-2008; Public Affairs Committee, Society for Neuroscience, 2001-2005; Scientific Advisory Board, Max-Planck Insititute for Neurobiology, 2001-2011, chair, 2006-2011; Elected to National Academy of Science, USA, 2002; Searle Scholars Advisory Board, 2003-2006, chair, 2005-2006; Visiting Committee, Duke Neurobiology Department, 2003, 2010; Scientific Advisory Board, Ataxia-Telangiectasa Children’s Project, 2003-; Scientific Advisory Board, Howard Hughes Medical Institute, 2004-; Viktor Hamburger Memorial Lecture, U. Wurzburg, 2004; Co-organizer of Cold Spring Harbor Meeting on Axon Guidance and Neural Plasticity, 2004; Co-organizer of Cold Spring Harbor Meeting on Neural

Imaging, 2005 and 2007; Picower lecture, MIT, 2005; Program Committee, International Brain Research Organization (IBRO), 2005; Liu Lecture, U. Penn., 2005; Champalimaud Foundation Vision Award, Jury, 2005-; Advisory Board, Institute of Neuroscience, Shanghai, China, 2006-2011; Human Embryonic Stem Cell Research Advisory Committee, National Academy of Sciences, 2006-2008; Scientific Advisory Board, Stowers Institute, 2006-; American Academy of Arts and Sciences, 2006-; Keynote speaker, Gordon Conference on Synaptic Transmission, 2008; Grass Lecture, Society for Neuroscience, 2008; Scientific Review Board, Charles A. King Trust, 2009-2013; Cold Spring Harbor/Asia Crick Symposium in Neuroscience, co-organizer, 2009; Advisory Board, Neuroscience Research Unit, McGill, Montreal General Hospital, and Montreal Neurological Institute, 2009 and 2013; Steering Committee, Edmund and Lily Safra Center for Brain Science, Jerusalem, 2009-, chair, 2013-; Sager Lecture (Friday night lecture), Woods Hole, 2009; Bishop Lecture, Washington University, 2010; Keynote speaker, Gordon Conference on Molecular and Cellular Neuroscience, 2010; Publication Committee, National Academy of Sciences, 2010-2014; Eckert Lecture, German

Neuroscience Society, 2011; NIH workshop on Molecular Anatomy: The Next Decade, chair, 2011; Rachford Lecture, U. Cincinnati, 2011; Stadtler Lecturer, M.D. Anderson Medical Center, 2011; Rush Record Award and Lecture, Baylor, 2011; Keynote Speaker, Gordon Conference on Dendrites, 2011; Keynote Speaker, Gordon Conference on Visual System Development, 2012; Wellcome Trust, funding selection panel, 2012-2016; NINDS/NIH Leadership Review Committee, 2012; Neuroscience Peer Review Consortium, Co-chair, 2012- 2015; Harvey Lecture, 2012; Schmitt Lecture (MIT), 2013; Beams Lecture, U. Iowa, 2013; Neuroscience Program Advisory Committee, Morehouse School of Medicine, 2013-; Elected Member-at-Large, Section on Neuroscience, AAAS, 2013-; NIH Advisory Committee (working group) to plan the BRAIN Initiative, 2013-14; External Advisory Committee, McGovern Institute, 2013-; Agranoff Lecture (University of Michigan), 2014; Keynote speaker, FASEB Conference on Retinal Neurobiology and Visual Processing, 2014; Search

Committee, Director, NINDS, NIH, 2014; World Economic Forum, Council on Brain Research, 2014-2016; Advisory Committee, Audacious Goals Program, NEI, NIH, 2014-; NINDS/NIH “Blue Ribbon” Planning Committee, 2014; National Academy of Sciences, Committee on Science, Technology, and Law, 2015-, executive committee, 2016-; Chair, Section 24, National Academy of Sciences, 2015-2018; Rosensteil Prize Jury, 2015-; Visiting Committee, Cambridge Neuroscience, University of Cambridge, UK, 2016; Search Committee, BRAIN Initiative Director, NIH, 2016; National Academy of Sciences, Officer Nominating

Committee, 2016; NIH/NEI Leadership Review Committee, 2016; Keynote speaker, EMBO Symposium on Neuronal Remodeling, 2016; Scientific Advisory Board, Gurdon Institute, Cambridge, 2017-; Arnold M. Clark Memorial Lecture, University of Delaware, 2017; Vernon Mountcastle Lecture, Johns Hopkins University, 2017; Gruber Prize in Neuroscience, 2017.

C.  Contributions to Science

My research has been largely devoted to the topic of synapse formation. Using the neuromuscular junction, we identified molecular and cellular mechanisms that determine how pre- and postsynaptic elements differentiate to enable synaptic transmission. Using retina, we are now asking how neurites in a tangled neuropil connect with appropriate partners, forming the specific patterns of synaptic connectivity that underlie circuit function.

These studies have also led us address related issues, such as the nature of the deleterious changes that occur to retinal neurons with age or after injury, and the extent to which retinal neurons can be divided into discrete cell types. (Papers cited are chosen from a total of 375.)

1.  Presynaptic differentiation. As a postdoctoral fellow, I showed that extracellular material (basal lamina) in the synaptic cleft of the neuromuscular junction organizes the differentiation of regenerating nerve terminals. In my own lab, we identified bioactive components of the synaptic cleft, including s-laminin (now b2-laminin) and used genetic method to assess their roles, and those of their partners (e.g., other laminin and collagen chains) and receptors (including calcium channels and integrins), in developing synapses in vivo. We went on to identify other target-derived organizers of presynaptic differentiation (e.g., FGFs and SIRPs) and analyzed their roles in formation of both neuromuscular and centralsynapses.

a.      Sanes JR, Marshall LM and McMahan UJ: Reinnervation of muscle fiber basal lamina after removal of myofibers. Differentiation of regenerating axons at original synaptic sites. J. Cell Biol. 78:176-198, 1978.

b.      Hunter DD, Shah V, Merlie JP and Sanes JR: Laminin-like adhesive protein concentrated in the synaptic cleft of the neuromuscular junction. Nature 338:229-234, 1989.

c.      Noakes PG, Gautam M, Mudd J, Sanes JR and Merlie JP: Aberrant differentiation of neuromuscular junctions in mice lacking s-laminin/laminin β2. Nature 374:258-262, 1995.

d.      Umemori H, Linhoff MW, Ornitz DM, and Sanes JR: FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118:257-270, 2004.

2.  Postsynaptic differentiation. With long-time colleague and collaborator John Merlie, I asked how muscle- intrinsic and nerve-derived factors collaborate to organize the postsynaptic membrane of the neuromuscular junction. We demonstrated specialized transcriptional properties of synaptic nuclei in the multinucleated muscle fiber, an early example of local synthesis of synaptic components. We also analyzed roles of nerve- derived organizing molecules (e.g., agrin) and postsynaptic proteins (e.g., rapsyn, MuSK, dystrobrevin, LL5b and neurotransmitter receptors [AChRs] themselves) in aggregation of neurotransmitter receptors at the postsynaptic membrane. In the course of this work, we found that some proteins involved in postsynaptic specialization are also required for muscle stabilization, generating insights into the pathogenesis of muscular dystrophy. Finally, we extended our work to analyze receptor clustering at central inhibitory synapses.

a.      Merlie JP and Sanes JR: Concentration of acetylcholine receptor mRNA in synaptic regions of adult muscle fibres. Nature 317:66-68, 1985.

b.      Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP and Sanes JR: Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85:525-535, 1996.

c.    Grady RM, Teng H, Nichol MC, Cunningham JC, Wilkinson RS and Sanes JR: Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90:729-738, 1997.

d.     Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H and Sanes JR: Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 282:1321-1324, 1998.

3. Synaptic specificity. Over the past decade, we have used the retina to seek determinants of synaptic specificity. The retina is about as complicated as any other part of the brain but has advantages of accessibility and organization that suit it for this quest. Accordingly, we devoted considerable efforts to identifying, classifying and gaining genetic access to individual neuronal types so we can mark and manipulate them. We then used retina to identify novel recognition molecules (e.g., sidekicks) and to analyze their roles, as well as those of previously identified recognition molecules (e.g., dscams and cadherins) in wiring up the retina.

a.     Yamagata M, Weiner JA, and Sanes JR: Sidekicks: synaptic adhesion molecules that promote lamina- specific connectivity in the retina. Cell 110:649-660, 2002.

b.     Duan X, Krishnaswamy A, De la Huerta I, and Sanes JR. Type II cadherins guide assembly of a direction-selective retinal circuit. Cell 158:793-807, 2014.

c.     Krishnaswamy A, Yamagata M, Duan X, Hong YK, and Sanes JR. Sidekick 2 directs formation of a retinal pathway that detects differential motion. Nature 524:466-70, 2015.

d.     Peng Y-R, Tran NM, Krishnaswamy A, Kostadinov D, Martersteck EM and Sanes JR. Satb1 regulates Contactin 5 to pattern dendrites of a mammalian retinal ganglion cell. Neuron 2017: 95:869- 883.

4.Neural developm ent. Knowing that limitations to progress are often technological, we have worked to improve methods for visualizing and perturbing neurons. They include a method for using recombinant

retrovirus to analyze lineage in vivo. After validating the method in non-neuronal tissues (skin and yolk sac), we used it to analyze lineage in brain, spinal cord and sensory ganglia. We also generated and  characterized mouse lines that have been used in numerous labs to indelibly label neuronal subsets in single colors (the XFP lines) or with multiple colors (Brainbow lines). These innovations have been useful not only for our studies of synaptic development but also for investigating other aspects of neuronal development, including migration, arrangement and polarization of neurons, and morphogenesis of dendrites. We followed up these leads before returning to our core interest in synapses. In most cases, these studies were or are being followed up by former postdoctoral fellows in their own laboratories (e.g., Luskin at Emory, Kishi in Japan, Kay at Duke, Lefebvre at Hospital for Sick Children in Toronto, Livet at Institut de Vision in Paris, Cai at U. Michigan).

a.     Feng G, Mellor R, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW and Sanes JR: Imaging neuronal subset in transgenic mice expressing multiple spectral variants of GFP. Neuron 28:41-51, 2000.

b.     Livet J, Weissman TA, Kang H, Lu J, Bennis R, Sanes JR, and Lichtman JW. Brainbow: Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature, 450:56-62, 2007.

c.     Kay JN, Chu MW, Sanes JR. MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons. Nature. 483:465-9, 2012.

d.     Lefebvre, JL, Kostadinov, D, Chen WV, Maniatis, T and Sanes, JR. Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488:517-521, 2012.

5.Identifying and classifying neuronal types. The only realistic way to deal with the complexity of the nervous system –and thereby pave the way for understanding its development, function and dysfunction– is to group neurons into types, which can then be analyzed systematically and reproducibly. In recent years, we have focused increasing attention on this issue, using transgenic and transcriptomic methods, and applying them to both normal and diseased/injured tissue.

a.     Kim IJ, Zhang Y, Yamagata M, Meister M and Sanes JR: Molecular identification of a novel retinal cell type that responds to upward motion. Nature 452:478-482, 2008.

b.    Duan X, Qiao, M, Bei F, Kim I-J, He Z and Sanes JR. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 2015; 85:124

c.     Shekhar K, Lapan SW, Whitney IE, Tran NM, Macosko EZ, Kowalczyk K, Adiconis X, Levin JZ, Nemesh J, Goldman M, McCarroll SA, Cepko CL*, Regev A*, and Sanes JR*. Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell 166:1308-1323 [*co- corresponding authors]

d.     Martersteck EM, Hirokawa KE, Evarts M, Bernard A, Duan X, Li Y, Ng L, Oh SW, Ouellette N, Royall J, Stoecklin M, Wang Q, Zeng H, Sanes JR*, Harris JA* Diverse Central Projection Patterns Of Retinal Ganglion Cells. Cell Reports, 2017; 18:2058-2072. (* co-corresponding authors)

A complete list of publications can be found at My Bibliography  https://www.ncbi.nlm.nih.gov/sites/myncbi/1F52OW1RlnXAt/bibliography/42764326/public/?sort=date&directio n=descending

C. Research support

R37 NS029169 (Sanes PI) (NIH)                                                                                                 07/01/91-02/28/20

Synaptic Choices in the Retinotectal System

Supports molecular, imaging and electrophysiological studies on immunoglobulin superfamily molecules required for assembly of retinal circuits.

R01 EY022073 (Sanes. PI) (NIH)                                                                                                  07/1/15-06/30/20

Cell surface molecules that regulate arrangement of retinal neurons and arbors. (NIH/NEI)

Supports molecular, imaging and electrophysiological studies studies on factors responsible for regular arrangement of neurons and dendrites in retina.

R21NS104248       (Sanes PI) (NIH)                                                                                        09/01/17-08/31/2019

Cell type-specific vulnerability of neurons to axonal injury: comprehensive mapping of types and gene expression analyzed by high throughput single cell RNAseq

This project will use transcriptomic analysis seek changes in gene expression that distinguished between neurons that survive injury and those that do not.

R21EY028633 (Sanes PI) (NIH)                                                                                                09/01/17-08/31/2019

Defining cell types of foveal and peripheral retina by high-throughput, single-cell transcriptional profiling This project will use transcriptomic analysis to classify neurons in the non-human primate retina, seeking

parallels to mouse retina as well as differences between peripheral and foveal cell types. (Awaiting funding, but scored in first percentile)