Professor of Developmental Neuroscience
Fellow of Gonville and Caius
Biography:
Christine Holt received a BSc Hons degree in Biological Sciences from the University of Sussex in 1977 and was awarded a PhD degree in Zoology from King’s College, London University in 1982. She did her postdoctoral training in the Physiology Department at Oxford University where she was also a Junior Research Fellow at Worcester College, and in the Biology Department at the University of California San Diego (UCSD). In 1992, she joined the faculty at UCSD and became a tenured Associate Professor in 1996. In 1997, she moved to the University of Cambridge as a Lecturer in the Anatomy Department and a Fellow of Gonville and Caius College. In 2003 she became the Professor of Developmental Neuroscience in the Department of Physiology, Development and Neuroscience. She was a Pew Scholar and a McKnight Scholar in her early career and has been the recipient of grant awards from the NIH, MRC, HFSP and Wellcome Trust and an ERC Advanced Grant. She serves on several Advisory Boards, Editorial Boards and Selection Committees. She was awarded The Remedios Caro Almela Prize for Research in Developmental Neurobiology (2011), the Champalimaud Vision Award (2016) and the Ferrier Medal (2017). She was elected Member of EMBO (2006), Fellow of the Medical Academy of Sciences (2007), Fellow of The Royal Society (2009) and Fellow of the Royal Society of Biology (2011).
Research Interests
Wiring the brain: RNA-based mechanisms of axon guidance and maintenance
My laboratory is investigating how nerve connections are formed and maintained. In the vertebrate visual system, neurons in the eye extend axons over long distances to find their synaptic targets in the brain. This impressive navigational feat which occurs during embryonic development underlies the precise wiring of the mature brain and is essential for building functional nerve connections. The goal of our research is to understand the molecular and cellular mechanisms that guide and maintain axon growth. We use a multidisciplinary experimental approach that involves in vivo gene transfer, growth cone chemotropic assays and time-lapse imaging of live axons in the brain. We focus in particular on the steering points within the visual pathway where axons alter their direction of growth and/or their behaviour such as the optic disc, the optic chiasm and the site of target entry. We have found, for example, that ephrin-B is important in regulating the divergent routing of axons at the chiasm and that netrin-1/DCC/laminin-1 interactions play a key role in directing axons out of the eye. Our studies have also revealed that the growing tips of axons, the growth cones, rapidly synthesize new proteins in response to encounters with guidance cues such as netrin-1. Inhibition of this local protein synthesis blocks the turning responses of growth cones in a chemotropic gradient suggesting that local translation of mRNAs is involved in directional steering. By understanding the molecular and cellular mechanisms that guide axon growth in development we aim to understand how nerve connections are first established. Basic knowledge of this sort is essential for the development of clinical therapies in nerve repair and for understanding neurodevelopmental and neurodegenerative disorders.
Main sources of funding: ERC Advanced Principal Investigator Grant, EMBO, Wellcome Trust.
Colleagues
Hovy Wong (PhD Student)
Roberta Cagnetta (PhD Student)
Benita Turner-Bridge (PhD Student)
Julie Qiaojin Lin (PhD Student)
Max Koppers (Postdoctoral Fellow)
Jean-Michel Cioni (Postdoctoral Fellow)
Toshiaki Shigeoka (Senior Postdoctoral Fellow)
Asha Dwivedy (Senior Research Associate)
Katrin Mooslehner (Research Associate)
Thomasz Dyl (Research Technician)
Main collaborators
Bill Harris (PDN, Cambridge University)
Kristian Franze and Jochen Guck (PDN and Physics, Cambridge)
James Fawcett (Brain Repair Centre, Cambridge)
Peter St George-Hyslop (Clinical School, Cambridge)
Clemens Kaminski (Department of Chemical Engineering and Biotechnology, Cambridge)
Eric Miska (Gurdon Institute, Cambridge)
Hosung Jung (Yonsei University, Seoul, S. Korea)
Jeroen Krijgsveld (EMBL, Germany)
Key Publications
Ströhl, F, Lin, QJ, Laine, RF, Wong, HH, Urbancic,V, Cagnetta, R, Holt, CE, Kaminski, CF, (2017), Single Molecule Translation Imaging Visualizes the Dynamics of Local β-Actin Synthesis in Retinal Axons, Scientific Reports 7(1):709 06 Apr
Wong HH, Lin JQ, Ströhl F, Roque CG, Cioni, JM, Cagnetta R, Turner-Bridger B, Laine R, Harris WA, Kaminski CF, Holt CE, (2017), RNA docking and local translation regulate site-specific axon remodelling in vivo, Neuron Aug 16; 95(4):852-868.e8
Shigeoka T, Jung H, Jung J, Turner-Bridger, B, Ohk J, Lin JQ, Amieux PS, Holt CE, (2016), Dynamic axonal translation in developing and mature visual circuits, Cell, pii: S0092-8674(16)30580-3. doi: 10.1016/j.cell.2016.05.029. [Epub ahead of print]
Konopacki FA, Wong HH, Dwivedy A, Bellon A, Blower MD, Holt CE, (2016), ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis, Open Biology Apr 20; 6: DOI: 10.1098/rsob.150218
Roque CG, Wong HH, Lin JQ, Holt CE, (2016), Tumor protein Tctp regulates axon development in the embryonic visual system, Development 143, 1134-1148
Murakami T, Qamar S, Lin JQ, (et al 23 authors), Holt CE, Vendruscolo M, Kaminski CF, St George-Hyslop P, (2015), ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function, Neuron 18;88(4):678-90
Piper M, Lee AC, van Horck FP, McNeilly H, Lu TB, Harris WA, Holt CE, (2015), Differential requirement of F-actin and microtubule cytoskeleton in cue-induced local protein synthesis in axonal growth cones, Neural Dev 10:3
Jung H, Gkogkas CG, Sonenberg N, Holt CE, (2014), Remote control of gene function by local translation, Cell 27;157 (1):26-40. Invited Review
Falk, J, Konopacki, FA, Zivraj, KH, Holt, CE, (2014), Rab5 and Rab4 regulate axon elongation in the Xenopus visual system, J. Neurosci 8;34(2):373-91
Kalous A, Stake JI, Yisraeli JK, Holt CE, (2013), RNA-binding protein Vg1RBP regulates terminal arbor formation but not long-range axon navigation in the developing visual system, Dev Neurobiol doi: 10.1002/dneu.22110
Holt CE, Schuman EM, (2013), The central dogma decentralized: new perspectives on RNA function and local translation in neurons, Neuron, 80(3):648-57. Invited review
Shigeoka T, Lu B, Holt CE, (2013), Cell biology in neuroscience: RNA-based mechanisms underlying axon guidance, J Cell Biol 202(7):991-9. Invited review
Hörnberg H, Wollerton-van Horck F, Maurus D, Zwart M, Svoboda H, Harris WA, Holt CE, (2013), RNA-binding protein Hermes/RBPMS inversely affects synapse density and axon arbor formation in retinal ganglion cells in vivo, J Neurosci 33(25):10384-95
Baudet M-L, Bellon A, Holt CE, (2013), Role of microRNAs in Semaphorin function and neural circuit formation , Seminars in Cell and Developmental Biology 24, 3, 146 – 155
Leung LC, Urbancic V, Baudet ML, Dwivedy A, Bayley TG, Lee AC, Harris WA, Holt CE, (2013), Coupling of NF-protocadherin signaling to axon guidance by cue-induced translation, Nature Neurosci, 16:166-73
Jung H, Yoon BC, Holt CE, (2012), Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair, Nature Reviews Neuroscience, 13:308-24
Yoon BC, Jung H, Dwivedy A, O’Hare CM, Zivraj KH, Holt CE, (2102), Local translation of extranuclear lamin B promotes axon maintenance, Cell, 148:752-64
Baudet, M-L, Zivraj K, Abreu-Goodger C, Muldal A, Armisen J, Blenkiron C, Goldstein LD, Miska EA, Holt CE, (2011), miR-124 acts via CoREST to control onset of Sema3A sensitivity in navigating retinal growth cones, Nature Neuroscience, 15:2-38
Jung H, O'Hare CM, Holt CE, (2011), Translational regulation in growth cones, Curr Opin Genet Dev, 21:458-64
Gumy LF, Yeo GSH, Tung Y-CL, Zivraj K, Willis D, Coppola G, Lam BYH, Twiss JL, Holt CE, Fawcett JW, (2011), Global transcriptome analysis reveals differences between embryonic and adult dorsal root ganglion axonal mRNAs that are implicated in axonal growth and pain, RNA, 17:85-98
Jung H, Holt CE, Local translation of mRNAs in neural development, WIREs RNA, Vol 1
Zivraj K, Tung L, Piper M, Gumy L, Fawcett J, Yeo G, Holt CE, (2010), Subcellular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs, J Neurosci 30:15464-78
Drinjakovic J, Jung H, Campbell DS, Strochlic L, Holt CE, (2010), E3 ligase Nedd4 promotes axon branching by down-regulating PTEN, Neuron, 65:341-57
Holt CE, Bullock S, (2009), Subcellular mRNA Localization in Animal Cells and Why it Matters, Science, 326:1212-6
Wizenmann et al, (2009), Extracellular Engrailed participates in the topographic guidance of retinal axons in vivo, Neuron, 12:355-66
Lin AC, Tan CL, Lin C-L, Strochlic L, Huang Y-S, Richter JD, Holt CE, (2009), Cytoplasmic polyadenylation and CPE-dependent mRNA regulation are involved in Xenopus retinal axon development, Neural Development, 4:8
Leung K-M, Holt CE, (2008), Live visualization of protein synthesis in axonal growth cones by microinjection of photoconvertible Kaede into Xenopus embryos, Nature Protocols, 3:1318-27
Piper M, Dwivedy A, Leung L, Bradley RS, Holt CE, (2008), NF-protocadherin and TAF1 regulate retinal axon initiation and elongation in vivo, J Neurosci, 28:100-5
Lin AC, Holt CE, (2007), Local translation and directional steering in axons. MiniReview, EMBO J, 26:3729-36
Leung K-M, van Horck FPG, Andrew C Lin, Allison R, Standart N, Holt CE, (2006), Asymmetrical b-actin mRNA translation in growth cones mediates attractive turning to netrin-1, Nature Neuroscience, 9:1247-56
Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, Leung K-M, Cogill E, Holt C, (2006), Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones, Neuron, 49:215-28
Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris WA, Prochiantz A, Holt CE, (2005), The transcription factor Engrailed-2 guides retinal axons, Nature, 438:94-98
Piper M, Salih S, Weinl C, Holt CE, Harris WA, (2005), Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation, Nature Neuroscience, 8:179-86
Piper M, Holt CE, (2004), RNA Translation in Axons, Annual Review of Cell and Developmental Biology, 20:505-23
Shewan DS, Dwivedy A, Anderson R, Holt CE, (2002), Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway, Nature Neuroscience, 5:955-62
Mann F, Ray S, Harris WA, Holt CE, (2002), Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signalling through ephrin-B ligands, Neuron, 35:461-73
Campbell DS, Holt CE, (2001), Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation, Neuron, 32:1013-26
Nakagawa S-I, Brennan C, Johnson K, Shewan D, Harris WA, Holt CE, (2000), Ephrin-B regulates the ipsilateral routing of retinal axons at the optic chiasm, Neuron, 25:599-610
Hoepker VH, Shewan D, Tessier-Lavigne M, Poo M-M, Holt CE, (1999), Growth cone attraction to netrin-1 is converted to repulsion by laminin-1, Nature, 401:69-73