One of the focus areas of Associate Professor Helen Cooper’s laboratory is to understand the molecular mechanisms underpinning correct formation of the cortex during embryonic development, as incorrect formation can result in developmental defects linked to schizophrenia, autism and epilepsy.
Cooper has recently identified that RYK has a critical role in the defining the architecture of the cortex, a process essential for advanced cognitive functions.
The adult human brain contains approximately 1011 neurons which make an estimated 1014 synaptic connections. How is such a astonishing structure generated? Cell and axon migration are fundamental processes essential for establishing the architectural plan of the central nervous system during vertebrate embryogenesis. Newly born neurons migrate along predefined pathways to establish the variety of distinct structures present in the adult brain. In addition, young neurons must also extend axons to their appropriate targets in order to establish the extensive network of connections found between neurons in the adult brain. Research in the Neural Migration Laboratory focuses on the molecular signalling systems governing neural differentiation, migration and axon pathfinding in the embryonic brain. This team has now identified several important cell surface receptors essential for these developmental processes. Current research is aimed at discovering how these receptors function during key phases of nervous system development. To address these questions we use both the mouse and zebrafish as our developmental models.
Neural tube formation
The earliest neural structure in the vertebrate is the neural tube, comprising a single layer of neural stem cells surrounding a central lumen. Mutations in our receptors produce neural tube defects which closely resemble the congenital neural tube abnormalities seen in humans.
Formation of the neocortex
The intricate neural architecture of the 6-layered mammalian neocortex is dependent on the ability of neural stem cells to differentiate into new neurons. These young neurons must then migrate into the correct cortical layers. In humans, mutations in genes controlling these processes have severe consequences for cortical development leading to intractable epilepsy, mental retardation, schizophrenia, dyslexia and autism.
Axon navigation in the growing brain
The corpus callosum is the major axon tract connecting the left and right hemispheres in the human cortex. There are more than 50 different human congenital syndromes, often associated with mental retardation and epilepsy, in which this axon tract fails to develop. This project may identify molecular targets that can be manipulated to encourage axon regrowth and correct pathfinding in the damaged adult human brain and spinal chord.
The adult brain contains neural stem cells that continue to make new neurons throughout life. Research in the Cooper lab has identified signalling molecules that may be harnessed to promote the birth of new neurons and their migration to damaged regions of the brain. The development of effective endogenous stem cell-based therapeutic strategies to promote neurogenesis and migration would be a major step forward in achieving functional recovery in the damaged brain.
- Keeble TR, Halford MM, Seaman C, Kee N, Anderson RB, Macheda M, Stacker SA, Cooper HM. The Wnt receptor, Ryk, is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum. J Neurosci 26:5840-5848, 2006. * Awarded the Australasian Neuroscience Society Paxinos-Watson Prize, 2007
- Fitzgerald DP, Cole SJ, Hammond A, Seaman C, Cooper HM. Characterization of Neogenin-expressing neural progenitor populations and migrating neuroblasts in the embryonic mouse forebrain. Neuroscience 142:703-716, 2006.
- de Vries M, Cooper HM. Emerging roles for neogenin and its ligands in CNS development. J Neurochem 106:1483-1492, 2008.
- Xu ZP, Niebert M, Walker TL, Porazik K, Cooper HM, Middleberg APJ, Grey PP, Bartlett PF, Lu GQ. Subcellular compartment targeting of layered double hydroxide nanoparticles. J Controlled Release 130:86-94, 2008.
- Kee N, Wilson N, de Vries M, Bradford D, Key B, Cooper HM. Neogenin and RGMa control neural tube closure and neuroepithelial morphology by regulating cell polarity. J Neurosci 28:12643-12653, 2008.
- Wong Y, Markham K, Xu ZP, Chen M, Lu GQ, Bartlett PF, Cooper HM. Efficient delivery of siRNA to cortical neurons using layered double hydroxide nanoparticles. Biomaterials 518:3237-3253, 2010.
- Bradford D, Faull RLM, Curtis MA, Cooper HM. Characterization of the netrin/RGMa receptor Neogenin in neurogenic regions of the mouse and human forebrain. J Comp Neurol 518: 3237-3253, 2010.
- Manitt C, Mimee A, Eng C, Pokinko M, Stroh T, Cooper HM, Kolb B, Flores C. The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. J Neurosci 31:8381-8394, 2011.
- Wong Y, Cooper HM#, Zhang K, Chen M, Bartlett PF, Xu ZP#. Efficiency of layered double hydroxide nanoparticle-mediated delivery of siRNA is determined by nucleotide sequence. J Colloid Interface Sci 369: 453-459, 2012. # Corresponding Authors
- Clark C, Nourse C, Cooper HM. The tangled web of noncanonical Wnt signalling in neural migration. NeuroSignals 20: 202-220, 2012.
- Chen M, Cooper HM#, Zhou JZ, Bartlett PF, Xu ZP#. Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery. J Colloid Interface Sci 390: 275-281, 2013. # Corresponding Authors
- Kee N, Wilson N, Key B, Cooper HM. Netrin-1 is required for efficient neural tube closure. Dev Neurobiol 73: 176-187, 2013
- O’Leary CJ, Cole SJ, Langford M, Hewage J, White A, Cooper HM. RGMa regulates cortical interneuron migration and differentiation. PLoS One 8:e81711, 2013.
- Manitt C, Eng C, Pokinko M, Ryan R, Torres-Berrío A, Lopez J, Yogendran S, Daubaras M, Dr. Grant A, Schmidt E, Tronche F, Krimpenfort P, Cooper HM, Pasterkamp J, Kolb B, Turecki G, Wong T-P, Nestler E, Giros B, Flores C. DCC orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients. Transl Psychiatry. 3:e338, 2013.
- Clark CEJ, Richards LJ, Stacker SA, Cooper HM. Wnt5a induces Ryk-dependent and -independent effects on callosal axon and dendrite growth. Growth Factors 32:11-17, 2014.
- Clark CEJ, Liu Y, Cooper HM. The Yin and Yang of Wnt/Ryk axon guidance in development and regeneration. Sci China Life Sci 57:366-371, 2014.
- O’Leary CJ, Bradford D, Chen M, White A, Blackmore DG, Cooper HM The Netrin/RGM receptor, Neogenin, controls adult neurogenesis by promoting neuroblast migration and cell cycle exit. Stem Cells 33:503-514, 2015.