Brain: Neurodevelopmental Genetics

Abstract

Genes expressed during development regulate the emergent structure and function of the growing brain. Genetic mechanisms interact with environmental influences to predispose individuals to structural and functional brain disorders. The embryological sequence of nervous system development is relatively well understood. Longitudinal neuroimaging studies have highlighted that prolonged postnatal brain change is associated with acquisition of higher level cognitive skills such as language, memory and executive function. However, understanding of developmental neurobiology has not yet been extensively integrated with systems neuroscience, to identify key molecular and cellular mechanisms relevant to human cognition. Furthermore, little is known about genetic variants that constrain embryological and later brain development to influence neurological and cognitive outcomes in developmental disabilities and psychiatric disorders. Following the completion of the Human Genome Project, new technologies have enabled an extraordinary expansion in knowledge of genetic sequence variation, gene expression and epigenetics. Establishing convergence between developmental biology, systems neuroscience and genomics to understand the neurobiological bases for neurodevelopmental disorders remains an exciting challenge for the next decades.

Key Concepts:

  • Brain development involves differentiation of highly specialised cell types, in predictable temporal sequences, and their organisation into precise spatial systems.

  • Genetic variation interacts with environmental influences to predispose individuals to structural and functional brain disorders, by influencing developmental mechanisms.

  • Major events in early nervous system development include induction of the neural plate, neurogenesis, differentiation of neuronal and glial cell types, and migration of cells into their correct position.

  • Postnatal brain development, including maturation of white matter tracts and synaptic pruning in response to stimulation and behaviour, is also important, but the neurobiology is much less well understood.

  • Both early and later developmental processes may be disrupted by genetic mutations or influenced by sequence variation, but links from gene to brain to cognitive functions are complex and require investigation by convergent methods.

  • New methods of investigating genomic organisation and the structure and function of the living human brain are increasingly being integrated to elucidate molecular and cellular mechanisms of relevance to neurodevelopmental disorders.

Keywords: development; brain; neurodevelopmental; neurobiology; disorders

Figure 1.

Specification of the neural plate. The two‐layered germ disc is converted to a three‐layered structure at gastrulation, through ingression of cells from the epiblast through the primitive streak. As the node regresses and the notochord extends within the developing mesodermal layer, increasingly posterior regions of the epiblast are exposed to neural‐inducing substances. By day 20, a thickened neural plate has emerged within the ectodermal layer.

Figure 2.

Regional patterning of the neural tube. The neural tube is patterned along its anterior–posterior (A–P) and dorsal–ventral (D–V) axes through expression of a three‐dimensional matrix of transcription factors. In the A–P axis, nested Hox gene expression defines the boundaries of each hindbrain segment (rhombomere), as well as the hindbrain–midbrain and midbrain–forebrain boundaries. In the D–V axis, signals including Sonic‐hedgehog and BMP‐7 diffuse from surrounding structures to define pools of hindbrain neuronal progenitors. The ventral pools will form motor neurons, while the dorsal precursors will be sensory.

Figure 3.

Neurogenesis and cortical migration. Neural stem cells are tethered to the ventricular surface of the neural tube. Here, they undergo vertical division to increase the size of the progenitor pool. When a horizontal division occurs, a new neuronal precursor migrates along the axons of radial glia through permissive substrate and through layers of older cells. When the new cell reaches a restricting substance (e.g. Reelin), it can travel no further and settles in a laminar position where it will differentiate and become part of the emerging functional circuitry. Some neurons travel into the cortex along tangential pathways, and a proportion of these cells become inhibitory interneurons.

Figure 4.

Axon guidance and topographic connections. Growth cones project towards far‐distant targets while retaining spatial order defined at their origin. They utilise complementary and competing molecular gradients at every stage of the journey: adhesion factors within the bundle (fascicle) of outgrowing axons, short‐range cues within the substrate through which they extend, long‐range signals from the target and from signalling stations along the route and ligand–receptor pairing at the target. The control of guidance cue expression gradients is probably both genetic and epigenetic.

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Baker, Kate D, and Skuse, David H(Sep 2010) Brain: Neurodevelopmental Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005145.pub2]