During early stages of nervous system development in vertebrates, neural tissue is subdivided into building blocks, each with a distinct regional identity. Within these subdivisions, the proliferation and differentiation of progenitor cells is regulated in time and space to form the correct number and organisation of neuronal and glial cells.
We are studying how these precise patterns form and are maintained through the regulation of cell identity and segregation by intercellular signaling.
Our studies focus on the hindbrain, which is subdivided to form a series of segments that each have a distinct and homogeneous identity. A sharp border forms at the interface of hindbrain segments, across which cells do not intermingle. Subsequently, a stereotyped pattern is formed within segments in the zebrafish hindbrain, in which the generation of neurons becomes confined to zones adjacent to segment boundaries. We are studying mechanisms that underlie the formation of sharp and homogeneous segments, and the roles of boundaries in the organisation of neurogenesis.
We have shown that signaling through Eph receptors and ephrins drive cell segregation that underlies the formation of sharp borders between segments. We are using genome modification and imaging of cell behaviour in zebrafish embryos to study the pathways downstream of Ephs and ephrins that segregates cells. In addition, we use cell culture assays and mathematical modelling that enables analysis of biochemical mechanisms and cell behaviour.
Our studies have shown that at very early stages some cells intermingle between hindbrain segments and switch identity to match their new neighbours. We have elucidated the underlying mechanism which involves a community regulation of retinoic acid signaling that controls segmental identity.
In related work, we have found that signaling from hindbrain boundaries has an important role in organising neurogenesis. Chemorepulsion from boundaries maintains a cluster of neurons in the centre of each segment which express fgf20, that in turn locally inhibits neurogenesis. We are further studying how fgf20 functions, and carrying out single cell transcriptome analysis to identity additional components of the network that regulates the pattern of cell differentiation within segments.