Autism, Fragile X Syndrome and intellectual disabilities can be viewed as disorders of neurodevelopment, whether with a genetic, environmental or multifactorial basis. To fulfil its many complex functions, the brain, and in particular the cerebral cortex, requires an enormous variety of different neuronal subtypes, far more than in any other part of the body.
Early brain development depends critically on high-level control of complex gene regulatory networks by a relatively small group of transcription factors and the interface upon which the different cell types interact: the cell membrane proteins and the extracellular matrix. How transcription factors, cell membrane proteins and extracellular matrix regulate development, whether of the brain or of other tissues, remains largely unanswered; however, because defects in these components can cause abnormal neurodevelopment, closing this significant knowledge gap would increase our understanding of many diseases.
The principal investigators of the Early Development group, all from the Centre for Integrative Physiology, take a multidisciplinary approach to understanding the molecular and cellular events of pre- and post-natal brain development — from the programming of neuronal subtype diversity to activity-dependent synaptic development. The fruit fly Drosophila melanogaster provides a relatively simple model organism in which to study transcriptional control of nervous system development. Much use is made of transgenic and knockout mouse models, particularly those deficient in, or expressing mutant versions of key transcription factors, such as Pax6, Gli3 and Foxg1. Pax6 is probably the most intensively studied transcription factor essential for normal mammalian brain development. In humans, PAX6 mutations cause eye defects but are also associated with a range of neurological and psychiatric conditions including autism and mental retardation. These conditions are linked to structural brain defects. Similar structural defects are often observed when the structure of the extracellular matrix heparan sulphate proteoglycans is disrupted, suggesting that there are networks linking the extracellular matrix and transcription factors. Understanding these multifactorial networks is a major challenge but has huge potential benefit for human health.