Professor Christine Holt FRS FMedSci

Christine Holt

University position

Professor

Professor Christine Holt FRS FMedSci is pleased to consider applications from prospective PhD students.

Departments

Department of Physiology, Development and Neuroscience

Email

ceh@mole.bio.cam.ac.uk

Home page

http://www.pdn.cam.ac.uk/staff/h...

Research Themes

Developmental Neuroscience

Cellular and Molecular Neuroscience

Interests

My laboratory studies how nerve connections are first established in the brain. Our studies 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 involves in vivo gene transfer, growth cone turning assays and time-lapse imaging of live axons in the brain. Our past studies have revealed that molecularly defined decision-points positioned along the pathway, such as the optic chiasm, guide axon growth. Recent studies have shown that hundreds of mRNAs reside in the growing tips of axons, the growth cones, and that local translation and degradation are important for axon guidance. Basic knowledge of this sort will be essential for developing clinical therapies in nerve repair and for understanding neurodevelopmental 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.
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

Keywords

growth cone

axon guidance

mRNA translation

retina

neural circuit

Clinical conditions

Axon regeneration and repair

Bipolar disorder

Neurodevelopmental disorders

Equipment

Cell culture

Confocal microscopy

Dynamic 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

Microscopy

Collaborators

Cambridge

James Fawcett

Bill Harris

Key publications

Leung K-M, van Horck FPG, Lin AC, Allison R, Standart N, Holt CE (2006), “Asymmetrical β-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 (2001), “Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation” Neuron 32:1013-1026

Publications

2011

Gumy 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

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

2010

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

2009

Holt 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

2008

Leung 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

2007

Dwivedy 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

2006

Ghosh 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

2005

Brunet 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

2004

Mann 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

2003

Campbell DS, Holt CE (2003), “Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones.” Neuron 37(6):939-52 Details

Mann 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

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

2002

Anderson 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

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

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

2001

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

Campbell 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

2000

Dingwell 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

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

1999

Harris WA, Holt CE (1999), “Neurobiology. Slit, the midline repellent.” Nature 398(6727):462-3 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

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

1998

Anderson 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

1997

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, 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

1996

Burns 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, 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

McFarlane S, Holt CE (1996), “Growth factors and neural connectivity.” Genet Eng (N Y) 18:33-47 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

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

1995

Chien 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

1994

Holt 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

1993

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, Harris WA (1993), “Position, guidance, and mapping in the developing visual system.” J Neurobiol 24(10):1400-22 Details

1992

Cornel E, Holt C (1992), “Precocious pathfinding: retinal axons can navigate in an axonless brain.” Neuron 9(6):1001-11 Details

1990

Harris 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

Holt CE, Garlick N, Cornel E (1990), “Lipofection of cDNAs in the embryonic vertebrate central nervous system.” Neuron 4(2):203-14 Details

1989

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

Thompson 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

1988

Holt 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

1987

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

1985

Harris 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

1984

Holt CE (1984), “Does timing of axon outgrowth influence initial retinotectal topography in Xenopus?” J Neurosci 4(4):1130-52 Details

1983

Holt CE (1983), “The topography of the initial retinotectal projection.” Prog Brain Res 58:339-45 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

1980

Holt C (1980), “Cell movements in Xenopus eye development.” Nature 287(5785):850-2 Details