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Professor Christine Elizabeth Holt FRSB FMedSci FRS

Professor Christine Elizabeth Holt,  FRSB FMedSci FRS

Professor of Developmental Neuroscience

Fellow of Gonville and Caius

Office Phone: +44 (0) 1223 766229, Fax: +44 (0) 1223 333786/840


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. In 2011, she was awarded The Remedios Caro Almela Prize for Research in Developmental Neurobiology. 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 disorders.

Main sources of funding: ERC Advanced Principal Investigator Grant, EMBO, Wellcome Trust.

Key Publications

Leung LC, Urbancic V, Baudet ML, Dwivedy A, Bayley TG, Lee AC, Harris WA, Holt CE, (2012), 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

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.