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Professor Christine Elizabeth Holt FRSB FMedSci FRS

Professor Christine Elizabeth Holt,  FRSB FMedSci FRS

Professor Emeritus of Developmental Neuroscience

Fellow of Gonville and Caius


Office Phone: +44 (0) 1223 766229

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 numerous grant awards from the NIH, MRC, HFSP and Wellcome Trust and ERC Advanced Grant. She continues to serve 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 Royal Society 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

Christine Holt studies 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 her research is to understand the molecular and cellular mechanisms that guide and maintain axons. She uses multidisciplinary experimental approaches such as in vivo gene transfer, growth cone chemotropic assays and time-lapse imaging of live axons in the brain, single molecule imaging and genome-wide analysis. She has focused 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. Her group 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. Her more recent studies have focused on local translation and mRNA localization in axons after her group discovered that the growing tips of axons, the growth cones, rapidly synthesize new proteins in response to guidance cues and that inhibition of axonal protein synthesis blocks directional guidance. Her group recently developed a subcellular genome-wide approach to investigate the mRNAs translated in axon terminals in vivo (Axon-TRAP-RNAseq) and showed that thousands of mRNAs are translated in both growing and mature retinal axons. Her group also provided some of the first evidence to show that axons are kept alive in vivo by the local synthesis of new proteins that help to sustain mitochondrial function, opening new approaches to neurodegeneration. By studying the cell biology of axons her work aims to gain a better understanding of how nerve connections are first established and how they are sustained throughout the lifetime of an animal. Fundamental knowledge of this sort is essential for understanding neurodevelopmental and neurodegenerative disorders and for developing clinical therapies in nerve repair.

Christine Holt became Professor Emeritus in 2019. She remains engaged in writing, reviewing and editing and in supervising research activities in PDN and at the Dementia Research Institute.

Main sources of funding: Wellcome Trust, Champalimaud Award

Colleagues

Toshiaki Shigeoka (postdoc)
Max Koppers (postdoc)
Roberta Cagnetta (postdoc)

Benita Turner-Bridge (postdoc)
Julie Qiaojin Lin (postdoc)
Katrin Mooslehner (Research Associate)

Main collaborators

Bill Harris (PDN, Cambridge)
Kristian Franze (PDN, Cambridge)
Giovanna Mallucci (Dementia Research Institute, Cambridge)
Clemens Kaminski (Department of Chemical Engineering and Biotechnology, Cambridge)
Peter St George-Hyslop (Clinical School, Cambridge)
Jeroen Krijgsveld (European Molecular Biology Laboratory (EMBL), Germany)

Key Publications

Cioni, J-M, JQ Lin, AV Holtermann, M Koppers, MAH Jakobs, A Azizi, B Turner-Bridger, T Shigeoka, K Franze, WA Harris and CE Holt. Late endosomes serve as platforms for mRNA translation in axons and promote mitochondrial and axonal integrity. Cell 2019 Jan 10;176(1-2):56-72.e15. Epub 2019 Jan 3. Highlighted in Spotlight Neuron 101, January 16, 2019.

Thompson AJ, Pillai EK, Dimov IB, Foster SK, Holt CE, Franze K. Rapid changes in tissue mechanics regulate cell behaviour in the developing embryonic brain. Elife. 2019 Jan 15;8. pii: e39356.

Shigeoka, T, M Koppers, Hovy H-W Wong, J Q Lin, A Dwivedy, J de F Nascimento, R Cagnetta, F van Tartwijk, F Ströhl, J-M Cioni, M Carrington, CF Kaminski, WA Harris, H Jung, CE Holt. On-site ribosome remodeling by locally synthesized ribosomal proteins in axons. bioRXiv Preprint posted : December 19, 2018. doi: https://doi.org/10.1101/500

Cagnetta, Roberta, Hovy Ho-Wai Wong, Christian K. Frese, Giovanna R. Mallucci, Jeroen Krijgsveld, Christine E. Holt. Noncanonical modulation of eIF2 pathway controls increase in local translation during neural wiring. Molecular Cell 2018 Dec 4. pii: S1097-2765(18)30983-3. [Epub ahead of print]

Turner-Bridger B, Jakobs M, Muresan L, Wong HH, Franze K, Harris WA, Holt CE. Single-molecule analysis of endogenous β-actin mRNA trafficking reveals a mechanism for compartmentalized mRNA localization in axons. Proc Natl Acad Sci U S A. 2018 Sep 25. pii: 201806189.

Leung, K-M, Bo Lu, Hovy Ho-Wai Wong, Benita Turner-Bridger, Christine E. Holt. Cue-polarized transport of β-actin mRNA depends on 3' UTR and microtubules in live growth cones. Frontiers in Cellular Neuroscience 2018 Sep 10;12:300. doi: 10.3389/fncel.2018.00300.

Cagnetta R, Frese CK, Shigeoka T, Krijgsveld J, Holt CE. Rapid Cue-Specific Remodeling of the Nascent Axonal Proteome. Neuron. 2018 Jul 11;99(1):29-46.e4. Epub 2018 Jun 28.

Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ, Phillips EC, Miyashita A, Williams D, Ströhl F, Meadows W, Ferry R, Dardov VJ, Tartaglia GG, Farrer LA, Kaminski Schierle GS, Kaminski CF, Holt CE, Fraser PE, Schmitt-Ulms G, Klenerman D, Knowles T, Vendruscolo M, St George-Hyslop P. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions. Cell. 2018 Apr 19;173(3):720-734.e15.

Cioni JM, Koppers M, Holt CE. Molecular control of local translation in axon development and maintenance. Curr Opin Neurobiol. 2018 Aug;51:86-94. Epub 2018 Mar 14. Review.

Cioni JM, Wong HH, Bressan D, Kodama L, Harris WA, Holt CE. Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function. Neuron. 2018 Mar 7;97(5):1078-1093.e6.

Wong HH, Lin JQ, Ströhl F, Roque CG, Cioni, JM, Cagnetta R, Turner-Bridger B, Laine R, Harris WA, Kaminski CF, Holt CE. RNA docking and local translation regulate site-specific axon remodelling in vivo. Neuron 95(4) Aug (2017).

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 AxonsScientific Reports7(1):709 06 Apr

Shigeoka T, Jung H, Jung J, Turner-BridgerB, Ohk J, Lin JQ, Amieux PS, Holt CE, (2016), Dynamic axonal translation in developing and mature visual circuitsCell, pii: S0092-8674(16)30580-3. [Epub ahead of print]

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 FunctionNeuron 18;88(4):678-90

Jung H, Gkogkas CG, Sonenberg N, Holt CE, (2014), Remote control of gene function by local translationCell 27;157 (1):26-40. Invited Review

Holt CE, Schuman EM, (2013), The central dogma decentralized: new perspectives on RNA function and local translation in neuronsNeuron, 80(3):648-57. Invited review

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 repairNature 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 maintenanceCell, 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 conesNature Neuroscience, 15:2-38

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 mRNAsJ Neurosci 30:15464-78

Drinjakovic J, Jung H, Campbell DS, Strochlic L, Holt CE, (2010), E3 ligase Nedd4 promotes axon branching by down-regulating PTENNeuron, 65:341-57

Holt CE, Bullock S, (2009), Subcellular mRNA Localization in Animal Cells and Why it MattersScience, 326:1212-6

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 conesNeuron, 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 axonsNature, 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 adaptationNature Neuroscience, 8:179-86

Shewan DS, Dwivedy A, Anderson R, Holt CE, (2002), Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathwayNature 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 ligandsNeuron, 35:461-73

Campbell DS, Holt CE, (2001), Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradationNeuron, 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 chiasmNeuron, 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-1Nature, 401:69-73

Above: Growth cone of retinal ganglion cell axon showing asymmetrical distribution of beta-actin after exposure to a 5 minute gradient of netrin-1 (top right). This spatial asymmetry is generated by local translation of beta-actin mRNA and is critical for attractive turning towards netrin-1 (see Leung et al, 2006).

Above: Single retinal ganglion cell in the embryonic visual system. The cell is stained with a dye (HRP) to reveal its soma and developing dendrites in the eye and its long axon extending across the midline (optic chiasm) into the contralateral optic tract. It is tipped with a motile growth process, the growth cone, which responds to guidance cues along the pathway and leads the axon to its final destination in the midbrain.

Above: in vivo timelapse imaging of retinotectal axon pathfinding in Xenopus laevis. Double-click for full screen view.

Above: Time-lapse movie showing beta-actin mRNA granules (pink) moving inside the growth cone of a retinal axon. The granules can be seen making excursions into the long thin filopodia, often in association with dynamic microtubules (green). (Movie made by Trina Bo Lu). Double-click for full screen view.