Born | Christine Elizabeth Holt 28 August 1954 |
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Alma mater | BSc in biological sciences, University of Sussex; PhD in zoology, King's College, London University |
Spouse | W.A. Harris |
Awards | Elected Member of EMBO (2005), Fellow of the Academy of Medical Sciences (2007), Fellow of the Royal Society (2009), Remedios Caro Almela Prize in Developmental Neurobiology (2011), Champalimaud Foundation Vision Award (2016), Rosenstiel Award (2022) |
Scientific career | |
Fields | Neuroscience |
Institutions | Professor of Developmental Neuroscience, University of Cambridge |
Website | http://www.pdn.cam.ac.uk/staff/holt/index.shtml |
Christine Elizabeth Holt CBE FRS FMedSci (born 28 August 1954) is a British developmental neuroscientist. [1]
She has been Professor of Developmental Neuroscience, University of Cambridge, [2] since 2003 and a Fellow of Gonville and Caius College, Cambridge University, [3] since 1997.
Holt is best known for her work in understanding the "basic mechanisms that govern how the vertebrate brain becomes wired up in the highly specific and complex way that it does." [4] In 2009, she was part of an international team that received a Human Frontiers Science Program grant to develop molecular probes that will help researchers better understand the "cellular GPS" system that guides neurons to create a properly wired nervous system." [5] Her research provides leads for future therapies for nerve damage and neurodevelopmental disorders. [1]
In 1977, Holt received her Bachelor of Science (Honors) in biological sciences from the University of Sussex. She did her doctoral work under the mentorship of John Scholes at King's College London, receiving her Ph.D in Zoology in 1982. [6]
From 1982 to 1986, she was a postdoctoral fellow in the Physiology Department at Oxford University and the Biology Department of the University of California San Diego (UCSD) under the mentorship W.A. Harris and Colin Blakemore. [6] [7] In 1986, she became an assistant research biologist and lecturer at UCSD, where she continued to study the frog visual system in its early embryonic period. She received a McKnight Scholar Award [4] for this work in 1986 and an Alexander von Humboldt award in 1987. [8]
She joined the faculty at UCSD in 1989. During this period, she studied the mechanism in which cells from the retina grow towards and make connections with specific brain cells, performing experiments to understand the role of adhesion molecules in axon guidance. Specifically, she assessed the loss of N-cadherin and integrins, two of the three types of adhesion molecules, on the embryonic brain. [8] In 1991, she was named a Pew Scholar.
In 1997, she moved to Gonville & Caius College at the University of Cambridge. [3] In 2003, she became a Professor of Developmental Neuroscience in the Department of Physiology, Development and Neuroscience, the position she still holds today. [9] She was elected a member of the European Molecular Biology Organization in 2005, a fellow of the Academy of Medical Sciences in 2007, and fellow of the Royal Society in 2009. [3] In 2011, she was awarded the Remedios Caro Almela Prize for Research in Developmental Neurobiology. [9] In 2016, she was part of a team awarded the António Champalimaud Vision Award, [10] along with John Flanagan of Harvard Medical School, Carol A. Mason of Columbia University, Carla Shatz of Stanford University. In 2017, Professor Holt was awarded the Ferrier Medal and Lecture by the Royal Society "for pioneering understanding of the key molecular mechanisms involved in nerve growth, guidance and targeting which has revolutionised our knowledge of growing axon tip." [11] In 2022 she received the Rosenstiel Award, [12] and in 2023 The Brain Prize. [13]
Christine Holt was elected Member of the National Academy of Sciences in April 2020. [14]
Holt's early career was spent studying cell movement during eye development in the frog visual system. Her seminal dissertation work was published in Nature 1980. [15] Much of what we currently know about the cellular and molecular mechanisms involved in establishing and sculpting the patterns of retinal projections comes from the work of Holt and her colleagues. [16]
Today, her research interests continue to lie in the mechanisms of axon guidance [7] and synaptic specificity in the development of complex brain networks. [1] Holt is credited as the pioneer of the idea that proteins synthesize and degenerate at a local level in an axon's cone of growth. [17] This process is required for accuracy in brain cell growth proper orientation. In addition to studying N-cadherin and integrins, she has also investigated the role of ephrins in axon growth and the formation of the optic chiasm. [18] In addition, her studies have found that netrin-1, DCC, and laminin-1 are key players in axon guidance from the retina. [19] [20] [21] For example, netrin-1 is both a chemoattractant and a chemorepellent for many classes of axons, and Holt's 1997 study shows that the growth cone of spinal neurons is chemoattractive to netrin-1 yet chemorepulsive when cAMP is present. [20] Currently, Holt collaborates with the lab of Giovanni Armenise at Harvard University, focusing on the role of microRNAs and non-coding RNAs in axon regrowth and wiring, and as a possible link to cancer of the nervous system. [22]
Holt is married to W.A. Harris (FRS). [23] Beyond teaching and research, she listed her other interests as “wildlife, walking, music, family”. [3]
"The Amazing Axon Adventure" http://www.cam.ac.uk/research/features/the-amazing-axon-adventure
An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.
A dendrite or dendron is a branched protoplasmic extension of a nerve cell that propagates the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. Electrical stimulation is transmitted onto dendrites by upstream neurons via synapses which are located at various points throughout the dendritic tree.
A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.
Axoplasm is the cytoplasm within the axon of a neuron. For some neuronal types this can be more than 99% of the total cytoplasm.
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.
Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, netrin resembles the extracellular matrix protein laminin.
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope. He first described the growth cone based on fixed cells as "a concentration of protoplasm of conical form, endowed with amoeboid movements". Growth cones are situated on the tips of neurites, either dendrites or axons, of the nerve cell. The sensory, motor, integrative, and adaptive functions of growing axons and dendrites are all contained within this specialized structure.
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before differentiation is complete.
Pioneer axon is the classification given to axons that are the first to grow in a particular region. They originate from pioneer neurons, and have the main function of laying down the initial growing path that subsequent growing axons, dubbed follower axons, from other neurons will eventually follow.
Ephrins are a family of proteins that serve as the ligands of the Eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).
Slit homolog 1 protein is a protein that in humans is encoded by the SLIT1 gene.
Andrew Gino Lumsden is an English neurobiologist, Emeritus Professor of the University of London and founder in 2000 of the Medical Research Council Centre for Developmental Neurobiology at King's College London.
Guidepost cells are cells which assist in the subcellular organization of both neural axon growth and migration. They act as intermediate targets for long and complex axonal growths by creating short and easy pathways, leading axon growth cones towards their target area.
Slit-Robo is the name of a cell signaling protein complex with many diverse functions including axon guidance and angiogenesis.
The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.
UNC is a set of proteins first identified through a set of screening tests in Caenorhabditis elegans, looking for roundworms with movement problems. Worms with which were un-coordinated were analysed in order to identify the genetic defect. Such proteins include UNC-5, a receptor for UNC-6 which is one of the netrins. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion (genetics) to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.
UNC-5 is a receptor for netrins including UNC-6. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.
Linda Richards is an Australian researcher at Queensland Brain Institute (QBI) at the University of Queensland.
Alain Chédotal is a French researcher specialising in the development of neural circuits. He has been a member of the French Academy of sciences since 2017.
Target selection is the process by which axons selectively target other cells for synapse formation. Synapses are structures which enable electrical or chemical signals to pass between nerves. While the mechanisms governing target specificity remain incompletely understood, it has been shown in many organisms that a combination of genetic and activity-based mechanisms govern initial target selection and refinement. The process of target selection has multiple steps that include axon pathfinding when neurons extend processes to specific regions, cellular target selection when neurons choose appropriate partners in a target region from a multitude of potential partners, and subcellular target selection where axons often target particular regions of a partner neuron.