Professor Christine Holt FMedSci FRS University positionProfessor Professor Christine Holt FMedSci FRS is pleased to consider applications from prospective PhD students. DepartmentsDepartment of Physiology, Development and Neuroscience Home pagehttp://www.pdn.cam.ac.uk/staff/h... Research ThemesInterestsMy laboratory studies how nerve connections are first established in the brain. We focus on the developing visual system and our main goal is to understand the molecular and cellular mechanisms of axon guidance that enable axons to navigate from the eye to their distant synaptic targets in the midbrain. We use a multidisciplinary experimental approach that includes in vivo gene manipulation, high-resolution live imaging of axons, gene profiling and chemotropic growth cone assays. Our past studies have revealed the existence of molecularly distinct decision-points along the pathway that guide axon growth. Our recent studies have shown that hundreds of mRNAs reside in axons and that local translation in response to extrinsic cues is a key regulatory mechanism in axon guidance, synapse formation and maintenance. By gaining a better understanding of how the CNS is assembled and maintained, our studies aim to provide fresh insight into neurodevelopmental and degenerative disorders.  Growth cone shows asymmetric beta-actin signal 5 minutes after onset of netrin-1 gradient (background gradient). Signal is highest (red) in filopodia closest to gradient source and is generated by local protein synthesis. View image full-size (2480x3532 pixels) Research Focus
EquipmentDynamic time-lapse imaging of gene-manipulated axons in vivo Fluorescence microscopy Immunohistochemistry In vivo gene transfer using lipofection, electroporation and blastomere injection Laser capture of cells and cell compartments (growth cone) for microarray analysis Live imaging of protein synthesis using TIRF microscopy Ribosome profiling and RNA-Seq analysis on axonal compartments Collaborators
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Key publicationsShigeoka T, Jung H, Jung J, Turner-Bridger, B, Ohk J, Lin JQ, Amieux PS, Holt CE. (in press), “Dynamic axonal translation in developing and mature visual circuits” Cell 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 Nov 18;88(4):678-90 Jung H, Gkogkas CG, Sonenberg N, Holt CE (2014), “Remote control of gene function by local translation.” Cell 157(1):26-40 Details Holt CE, Schuman EM (2013), “The central dogma decentralized: new perspectives on RNA function and local translation in neurons.” Neuron 80(3):648-57 Details Leung LC, Urban?i? 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.” Nat Neurosci 16(2):166-73 Details Jung H, Yoon BC, Holt CE (2012), “Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair.” Nat Rev Neurosci 13(5):308-24 Details Yoon BC, Jung H, Dwivedy A, O'Hare CM, Zivraj KH, Holt CE (2012), “Local translation of extranuclear lamin B promotes axon maintenance.” Cell 148(4):752-64 Details Baudet ML, Zivraj KH, Abreu-Goodger C, Muldal A, Armisen J, Blenkiron C, Goldstein LD, Miska EA, Holt CE (2011), “miR-124 acts through CoREST to control onset of Sema3A sensitivity in navigating retinal growth cones.” Nat Neurosci 15(1):29-38 Details Drinjakovic J, Jung H, Campbell DS, Strochlic L, Dwivedy A, Holt CE (2010), “E3 ligase Nedd4 promotes axon branching by downregulating PTEN.” Neuron 65(3):341-57 Details Zivraj KH, Tung YC, Piper M, Gumy L, Fawcett JW, Yeo GS, Holt CE (2010), “Subcellular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs.” J Neurosci 30(46):15464-78 Details Leung K-M, van Horck FPG, Lin AC, Allison R, Standart N, Holt CE (2006), “Asymmetrical ?-actin mRNA translation in growth cones mediates attractive turning to netrin 1” Nature Neuroscience 9 (10):1247-56 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 Campbell DS, Holt CE (2003), “Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones.” Neuron 37(6):939-52 Details Williams SE, Mann F, Erskine L, Sakurai T, Wei S, Rossi DJ, Gale NW, Holt CE, Mason CA, Henkemeyer M (2003), “Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm.” Neuron 39(6):919-35 Details Mann F, Ray S, Harris W, Holt C (2002), “Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrin-B ligands.” Neuron 35(3):461-73 Details Shewan D, Dwivedy A, Anderson R, Holt CE (2002), “Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway.” Nat Neurosci 5(10):955-62 Details Campbell DS, Holt CE (2001), “Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation.” Neuron 32(6):1013-26 Details Nakagawa S, Brennan C, Johnson KG, Shewan D, Harris WA, Holt CE (2000), “Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm.” Neuron 25(3):599-610 Details Höpker VH, Shewan D, Tessier-Lavigne M, Poo M, Holt C (1999), “Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.” Nature 401(6748):69-73 Details de la Torre JR, Höpker VH, Ming GL, Poo MM, Tessier-Lavigne M, Hemmati-Brivanlou A, Holt CE (1997), “Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC.” Neuron 19(6):1211-24 Details McFarlane S, Cornel E, Amaya E, Holt CE (1996), “Inhibition of FGF receptor activity in retinal ganglion cell axons causes errors in target recognition.” Neuron 17(2):245-54 Details Riehl R, Johnson K, Bradley R, Grunwald GB, Cornel E, Lilienbaum A, Holt CE (1996), “Cadherin function is required for axon outgrowth in retinal ganglion cells in vivo.” Neuron 17(5):837-48 Details Chien CB, Rosenthal DE, Harris WA, Holt CE (1993), “Navigational errors made by growth cones without filopodia in the embryonic Xenopus brain.” Neuron 11(2):237-51 Details Holt CE, Garlick N, Cornel E (1990), “Lipofection of cDNAs in the embryonic vertebrate central nervous system.” Neuron 4(2):203-14 Details Holt CE (1989), “A single-cell analysis of early retinal ganglion cell differentiation in Xenopus: from soma to axon tip.” J Neurosci 9(9):3123-45 Details Harris WA, Holt CE, Bonhoeffer F (1987), “Retinal axons with and without their somata, growing to and arborizing in the tectum of Xenopus embryos: a time-lapse video study of single fibres in vivo.” Development 101(1):123-33 Details Holt CE, Harris WA (1983), “Order in the initial retinotectal map in Xenopus: a new technique for labelling growing nerve fibres.” Nature 301(5896):150-2 Details Publications2016Konopacki 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 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 2015Piper 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 Development Feb 25;10:3. 2014Falk J, Konopacki FA, Zivraj KH, Holt CE (2014), “Rab5 and rab4 regulate axon elongation in the Xenopus visual system.” J Neurosci 34(2):373-91 Details Manns R, Schmandke A, Schmandke A, Jareonsettasin P, Cook G, Schwab ME, Holt C, Keynes R (2014), “Protein synthesis dependence of growth cone collapse induced by different Nogo-A-domains.” PLoS One 9(1):e86820 Details Sotelo-Silveira JR, Holt CE (2014), “Introduction to the special issue on local protein synthesis in axons.” Dev Neurobiol 74(3):207-9 Details 2013Baudet ML, Bellon A, Holt CE (2013), “Role of microRNAs in Semaphorin function and neural circuit formation.” Semin Cell Dev Biol 24(3):146-55 Details Hörnberg H, Holt C (2013), “RNA-binding proteins and translational regulation in axons and growth cones.” Front Neurosci 7:81 Details 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 Details 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 Details Shigeoka T, Lu B, Holt CE (2013), “Cell biology in neuroscience: RNA-based mechanisms underlying axon guidance.” J Cell Biol 202(7):991-9 Details 2012Leung L, Holt CE (2012), “Imaging axon pathfinding in zebrafish in vivo.” Cold Spring Harb Protoc 2012(9):992-7 Details Leung L, Holt CE (2012), “Imaging axon pathfinding in Xenopus in vivo.” Cold Spring Harb Protoc 2012(9):984-91 Details Manns RP, Cook GM, Holt CE, Keynes RJ (2012), “Differing semaphorin 3A concentrations trigger distinct signaling mechanisms in growth cone collapse.” J Neurosci 32(25):8554-9 Details 2011Gumy LF, Yeo GS, Tung YC, Zivraj KH, Willis D, Coppola G, Lam BY, Twiss JL, Holt CE, Fawcett JW (2011), “Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization.” RNA 17(1):85-98 Details Han L, Wen Z, Lynn RC, Baudet ML, Holt CE, Sasaki Y, Bassell GJ, Zheng JQ (2011), “Regulation of chemotropic guidance of nerve growth cones by microRNA.” Mol Brain 4:40 Details Jung H, O'Hare CM, Holt CE (2011), “Translational regulation in growth cones.” Curr Opin Genet Dev Details Yoon BC, Zivraj KH, Strochlic L, Holt CE (2011), “14-3-3 proteins regulate retinal axon growth by modulating ADF/cofilin activity.” Dev Neurobiol Details 2009Holt CE, Bullock SL (2009), “Subcellular mRNA localization in animal cells and why it matters.” Science 326(5957):1212-6 Details Lin AC, Tan CL, Lin CL, Strochlic L, Huang YS, Richter JD, Holt CE (2009), “Cytoplasmic polyadenylation and cytoplasmic polyadenylation element-dependent mRNA regulation are involved in Xenopus retinal axon development.” Neural Dev 4:8 Details Merianda TT, Lin AC, Lam JS, Vuppalanchi D, Willis DE, Karin N, Holt CE, Twiss JL (2009), “A functional equivalent of endoplasmic reticulum and Golgi in axons for secretion of locally synthesized proteins.” Mol Cell Neurosci 40(2):128-42 Details Vogelaar CF, Gervasi NM, Gumy LF, Story DJ, Raha-Chowdhury R, Leung KM, Holt CE, Fawcett JW (2009), “Axonal mRNAs: characterisation and role in the growth and regeneration of dorsal root ganglion axons and growth cones.” Mol Cell Neurosci 42(2):102-15 Details Yoon BC, Zivraj KH, Holt CE (2009), “Local translation and mRNA trafficking in axon pathfinding.” Results Probl Cell Differ 48:269-88 Details 2008Leung KM, Holt CE (2008), “Live visualization of protein synthesis in axonal growth cones by microinjection of photoconvertible Kaede into Xenopus embryos.” Nat Protoc 3(8):1318-27 Details Lin AC, Holt CE (2008), “Function and regulation of local axonal translation.” Curr Opin Neurobiol 18(1):60-8 Details Lin AC, Holt CE (2008), “Outsourcing CREB translation to axons to survive.” Nat Cell Biol 10(2):115-8 Details 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(1):100-5 Details Strochlic L, Dwivedy A, van Horck FP, Falk J, Holt CE (2008), “A role for S1P signalling in axon guidance in the Xenopus visual system.” Development 135(2):333-42 Details Van Horck FP, Holt CE (2008), “A cytoskeletal platform for local translation in axons.” Sci Signal 1(8):pe11 Details 2007Dwivedy A, Gertler FB, Miller J, Holt CE, Lebrand C (2007), “Ena/VASP function in retinal axons is required for terminal arborization but not pathway navigation.” Development 134(11):2137-46 Details Falk J, Drinjakovic J, Leung KM, Dwivedy A, Regan AG, Piper M, Holt CE (2007), “Electroporation of cDNA/Morpholinos to targeted areas of embryonic CNS in Xenopus.” BMC Dev Biol 7:107 Details Lin AC, Holt CE (2007), “Local translation and directional steering in axons.” EMBO J 26(16):3729-36 Details Piper M, van Horck F, Holt C (2007), “The role of cyclic nucleotides in axon guidance.” Adv Exp Med Biol 621:134-43 Details 2006Ghosh A, Holt CE (2006), “Development.” Curr Opin Neurobiol 16(1):1-4 Details Hussain SA, Piper M, Fukuhara N, Strochlic L, Cho G, Howitt JA, Ahmed Y, Powell AK, Turnbull JE, Holt CE, Hohenester E (2006), “A molecular mechanism for the heparan sulfate dependence of slit-robo signaling.” J Biol Chem 281(51):39693-8 Details Leung KM, van Horck FP, Lin AC, Allison R, Standart N, Holt CE (2006), “Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1.” Nat Neurosci 9(10):1247-56 Details Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, Leung KM, Cogill E, Holt C (2006), “Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones.” Neuron 49(2):215-28 Details 2005Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris W, Prochiantz A, Holt C (2005), “The transcription factor Engrailed-2 guides retinal axons.” Nature 438(7064):94-8 Details Holt CE, Dickson BJ (2005), “Sugar codes for axons?” Neuron 46(2):169-72 Details Piper M, Salih S, Weinl C, Holt CE, Harris WA (2005), “Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation.” Nat Neurosci 8(2):179-86 Details Rodriguez J, Esteve P, Weinl C, Ruiz JM, Fermin Y, Trousse F, Dwivedy A, Holt C, Bovolenta P (2005), “SFRP1 regulates the growth of retinal ganglion cell axons through the Fz2 receptor.” Nat Neurosci 8(10):1301-9 Details Verma P, Chierzi S, Codd AM, Campbell DS, Meyer RL, Holt CE, Fawcett JW (2005), “Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration.” J Neurosci 25(2):331-42 Details 2004Mann F, Harris WA, Holt CE (2004), “New views on retinal axon development: a navigation guide.” Int J Dev Biol 48(8-9):957-64 Details Ohta K, Lupo G, Kuriyama S, Keynes R, Holt CE, Harris WA, Tanaka H, Ohnuma S (2004), “Tsukushi functions as an organizer inducer by inhibition of BMP activity in cooperation with chordin.” Dev Cell 7(3):347-58 Details Piper M, Holt C (2004), “RNA translation in axons.” Annu Rev Cell Dev Biol 20:505-23 Details van Horck FP, Weinl C, Holt CE (2004), “Retinal axon guidance: novel mechanisms for steering.” Curr Opin Neurobiol 14(1):61-6 Details 2003Mann F, Miranda E, Weinl C, Harmer E, Holt CE (2003), “B-type Eph receptors and ephrins induce growth cone collapse through distinct intracellular pathways.” J Neurobiol 57(3):323-36 Details 2002Anderson RB, Holt CE (2002), “Expression of UNC-5 in the developing Xenopus visual system.” Mech Dev 118(1-2):157-60 Details Irie A, Yates EA, Turnbull JE, Holt CE (2002), “Specific heparan sulfate structures involved in retinal axon targeting.” Development 129(1):61-70 Details Walz A, Anderson RB, Irie A, Chien CB, Holt CE (2002), “Chondroitin sulfate disrupts axon pathfinding in the optic tract and alters growth cone dynamics.” J Neurobiol 53(3):330-42 Details 2001Campbell DS, Regan AG, Lopez JS, Tannahill D, Harris WA, Holt CE (2001), “Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones.” J Neurosci 21(21):8538-47 Details Harris B, Holt C (2001), “Stimulating new turns.” Neuron 29(2):311-2 Details Johnson KG, McKinnell IW, Stoker AW, Holt CE (2001), “Receptor protein tyrosine phosphatases regulate retinal ganglion cell axon outgrowth in the developing Xenopus visual system.” J Neurobiol 49(2):99-117 Details Mann F, Holt CE (2001), “Control of retinal growth and axon divergence at the chiasm: lessons from Xenopus.” Bioessays 23(4):319-26 Details Nutt SL, Dingwell KS, Holt CE, Amaya E (2001), “Xenopus Sprouty2 inhibits FGF-mediated gastrulation movements but does not affect mesoderm induction and patterning.” Genes Dev 15(9):1152-66 Details 2000Dingwell KS, Holt CE, Harris WA (2000), “The multiple decisions made by growth cones of RGCs as they navigate from the retina to the tectum in Xenopus embryos.” J Neurobiol 44(2):246-59 Details Johnson KG, Holt CE (2000), “Expression of CRYP-alpha, LAR, PTP-delta, and PTP-rho in the developing Xenopus visual system.” Mech Dev 92(2):291-4 Details 1999Harris WA, Holt CE (1999), “Neurobiology. Slit, the midline repellent.” Nature 398(6727):462-3 Details Ohnuma S, Philpott A, Wang K, Holt CE, Harris WA (1999), “p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus retina.” Cell 99(5):499-510 Details Ruchhoeft ML, Ohnuma S, McNeill L, Holt CE, Harris WA (1999), “The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo.” J Neurosci 19(19):8454-63 Details 1998Anderson RB, Walz A, Holt CE, Key B (1998), “Chondroitin sulfates modulate axon guidance in embryonic Xenopus brain.” Dev Biol 202(2):235-43 Details Holt CE, Harris WA (1998), “Target selection: invasion, mapping and cell choice.” Curr Opin Neurobiol 8(1):98-105 Details Lom B, Höpker V, McFarlane S, Bixby JL, Holt CE (1998), “Fibroblast growth factor receptor signaling in Xenopus retinal axon extension.” J Neurobiol 37(4):633-41 Details McFarlane S, Zuber ME, Holt CE (1998), “A role for the fibroblast growth factor receptor in cell fate decisions in the developing vertebrate retina.” Development 125(20):3967-75 Details Zhang LI, Tao HW, Holt CE, Harris WA, Poo M (1998), “A critical window for cooperation and competition among developing retinotectal synapses.” Nature 395(6697):37-44 Details 1997McFarlane S, Holt CE (1997), “Growth factors: a role in guiding axons?” Trends Cell Biol 7(11):424-30 Details Ming GL, Song HJ, Berninger B, Holt CE, Tessier-Lavigne M, Poo MM (1997), “cAMP-dependent growth cone guidance by netrin-1.” Neuron 19(6):1225-35 Details Walz A, McFarlane S, Brickman YG, Nurcombe V, Bartlett PF, Holt CE (1997), “Essential role of heparan sulfates in axon navigation and targeting in the developing visual system.” Development 124(12):2421-30 Details Worley TL, Cornel E, Holt CE (1997), “Overexpression of c-src and n-src in the developing Xenopus retina differentially impairs axonogenesis.” Mol Cell Neurosci 9(4):276-92 Details 1996Burns JC, McNeill L, Shimizu C, Matsubara T, Yee JK, Friedmann T, Kurdi-Haidar B, Maliwat E, Holt CE (1996), “Retrovirol gene transfer in Xenopus cell lines and embryos.” In Vitro Cell Dev Biol Anim 32(2):78-84 Details McFarlane S, Holt CE (1996), “Growth factors and neural connectivity.” Genet Eng (N Y) 18:33-47 Details Worley T, Holt C (1996), “Inhibition of protein tyrosine kinases impairs axon extension in the embryonic optic tract.” J Neurosci 16(7):2294-306 Details Worley TL, Holt CE (1996), “Expression and herbimycin A-sensitive localization of pp125FAK in retinal growth cones.” Neuroreport 7(6):1133-7 Details 1995Chien CB, Cornel EM, Holt CE (1995), “Absence of topography in precociously innervated tecta.” Development 121(8):2621-31 Details Harris WA, Holt CE (1995), “From tags to RAGS: chemoaffinity finally has receptors and ligands.” Neuron 15(2):241-4 Details Lilienbaum A, Reszka AA, Horwitz AF, Holt CE (1995), “Chimeric integrins expressed in retinal ganglion cells impair process outgrowth in vivo.” Mol Cell Neurosci 6(2):139-52 Details McFarlane S, McNeill L, Holt CE (1995), “FGF signaling and target recognition in the developing Xenopus visual system.” Neuron 15(5):1017-28 Details Thompson ID, Cordery P, Holt CE (1995), “Postnatal changes in the uncrossed retinal projection of pigmented and albino Syrian hamsters and the effects of monocular enucleation.” J Comp Neurol 357(2):181-203 Details 1994Holt CE, Lemaire P, Gurdon JB (1994), “Cadherin-mediated cell interactions are necessary for the activation of MyoD in Xenopus mesoderm.” Proc Natl Acad Sci U S A 91(23):10844-8 Details 1993Holt CE, Harris WA (1993), “Position, guidance, and mapping in the developing visual system.” J Neurobiol 24(10):1400-22 Details 1992Cornel E, Holt C (1992), “Precocious pathfinding: retinal axons can navigate in an axonless brain.” Neuron 9(6):1001-11 Details 1990Harris WA, Holt CE (1990), “Early events in the embryogenesis of the vertebrate visual system: cellular determination and pathfinding.” Annu Rev Neurosci 13:155-69 Details 1989Thompson I, Holt C (1989), “Effects of intraocular tetrodotoxin on the development of the retinocollicular pathway in the Syrian hamster.” J Comp Neurol 282(3):371-88 Details 1988Holt CE, Bertsch TW, Ellis HM, Harris WA (1988), “Cellular determination in the Xenopus retina is independent of lineage and birth date.” Neuron 1(1):15-26 Details 1985Harris WA, Holt CE, Smith TA, Gallenson N (1985), “Growth cones of developing retinal cells in vivo, on culture surfaces, and in collagen matrices.” J Neurosci Res 13(1-2):101-22 Details 1984Holt CE (1984), “Does timing of axon outgrowth influence initial retinotectal topography in Xenopus?” J Neurosci 4(4):1130-52 Details 1983Holt CE (1983), “The topography of the initial retinotectal projection.” Prog Brain Res 58:339-45 Details 1980Holt C (1980), “Cell movements in Xenopus eye development.” Nature 287(5785):850-2 Details |
