Regulation of boundary formation and neurogenesis

Lead Research Organisation: The Francis Crick Institute

Abstract

The organisation of the adult body arises by forming distinct tissues at the correct location, many of which become further subdivided. For tissues to be precisely organised, it is important that each region within it is not intermingled with its neighbours. This involves formation of a sharp boundary, which requires inhibition of cell intermingling between the adjacent regions. Disruption of the underlying mechanisms can contribute to disease, such as the invasive behaviour of tumour cells. In some tissues, boundaries localise special signaling cells that have an organising function.
We study boundary formation during development of a specific region of the nervous system – the hindbrain - and how these boundaries organise neurogenesis. Our studies revealed a crucial role of cell signaling mediated by proteins called Eph receptors and ephrins. We are studying how this signaling acts by using a combination of experiments in zebrafish, cell culture assays, and computer simulations. These studies reveal that Eph-ephrin signaling triggers cell repulsion that can segregate cells and sharpen borders.
The generation of the correct number of neurons requires that the differentiation of progenitor cells is regulated in time and space. In the zebrafish hindbrain, the generation of neurons becomes confined to zones that flank boundaries. Our studies show that this is organised by signaling from boundaries and from specific neurons.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

The complex organisation of the adult body arises by the generation of distinct tissues, many of which become subdivided into domains which each have a specific regional identity. For precisely organised patterns to be generated and maintained, it is important that each tissue, or region within it, is not intermingled with its neighbours. This is reflected by the formation of a sharp boundary between the adjacent cell populations that have distinct identity. In some tissues, sharp boundaries also act to localise specialised signaling cells which regulate the local pattern of cell differentiation. Sharp boundaries form despite the extensive intermingling of cells during growth and morphogenesis. The inhibition of such mixing across boundaries has a crucial role in stabilising many tissues during development, and also in the adult, and when disrupted can contribute to disease, such as the invasive behaviour of tumour cells.
We study molecular mechanisms underlying boundary formation during hindbrain development, and how these boundaries organise neurogenesis. Our studies revealed that signaling between Eph receptors and ephrins expressed in complementary domains underlies the segregation of cells and formation of sharp boundaries. We are using two approaches to analyse the mechanisms by which Eph-ephrin signaling acts: (1) gene editing, generation of transgenic reporter lines and in vivo imaging in zebrafish; (2) cell culture assays of segregation and boundary formation, in combination with computer simulations based on quantitative analysis of cell behaviour. These studies reveal that Eph-ephrin signaling triggers cell repulsion that can drive cell segregation and border sharpening.
The generation of the correct number of neurons and glia requires that the differentiation of neural progenitor cells is regulated in time and space. In the zebrafish hindbrain, neurogenesis becomes confined to neurogenic zones that flank hindbrain boundaries. Our studies show that this patterning is organised by chemorepulsive signaling from hindbrain boundaries which positions fgf20-expressing neurons at segment centres. The fgf20-expressing neurons in turn locally inhibit neurogenesis. We are studying the mechanisms by which fgf20 signaling regulates neurogenesis by identification and functional analyses of target genes.

Publications

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