Growth factor control of brain development...

The vertebrate embryo is sculpted largely through a process of persuasion rather than cell autonomy, where the persuasive forces take the form of intercellular signals. Our group seeks to identify these instructive cues and understand the mechanisms by which they direct cellular behaviours. We focus primarily upon how signalling processes direct development of the brain; how they are deployed to impart regional identity, cell fate, control proliferation and to direct morphogenetic movements, guide axons to their targets and determine synaptic phenotype.

Our recent work has established that the same signal from the same source may serve to instruct several of these processes either simultaneously or sequentially. Moreover, we have found that the same signalling centre may serve to direct the development of tissues adjacent to the brain, thereby coordinating head development both spatially and temporally. We make use of three vertebrate model organisms in our work, zebrafish, chick and mouse, according to which is best-suited to address any particular question and we also utilise organ, explant and tissue culture approaches. Some ongoing projects are introduced below and further details can be found on the web page of individuals in our group.

The vertebrate embryo is sculpted largely through a process of persuasion rather than cell autonomy, where the persuasive forces take the form of intercellular signals. Our group seeks to identify these instructive cues and understand the mechanisms by which they direct cellular behaviours. We focus primarily upon how signalling processes direct development of the brain; how they are deployed to impart regional identity, cell fate, control proliferation and to direct morphogenetic movements and guide axons to their targets. Our recent work has established that Neurulation

Failure of neural tube closure (neurulation) is a major source of human birth defects, the most severe form being craniorachyschisis, in which closure fails to initiate in the midbrain resulting in a complete failure of brain closure. We are studying a transmembrane receptor called Flamingo which, when defective, results in craniorachyschisis in mammals and defective neurulation in zebrafish. Nothing is known about how Flamingo signals within the cell, how it is activated and in which cells it is required during neurulation. We are currently seeking to address all of these problems.

Patterning the brain

During and immediately after neurulation, local signaling imparts regional identity to the brain. We have examined this in detail in the context of Fgf8, which signals from the boundary between midbrain and anterior hindbrain (the isthmus) to specify and pattern those two structures. We also established the generality of this mechanism, identifying similar Fgf-producing signalling centres in both forebrain and hindbrain. Currently we are seeking to use our in vivo studies with computer-based modeling to further understand and, most importantly, predict how regional patterning occurs. The latter studies are in collaboration with the Universty of Irvine in California.

Understanding FGF intracellular signalling pathways and their interaction with those of other extracellular cues.

Current work focuses on understanding the intracellular signalling pathways and their feedback inhibitors that mediate Fgf function particularly at the isthmus. We are also examining how cell fate and neural progenitor proliferation are regulated in these regions.

Such studies have led us to investigate how the multiple signals that impinge on neural progenitors are integrated within the cell. We are studying this problem in the context of Fgf, Wnt, BMP/GDF and Shh signals.

Connectivity

We have shown that Fgf8 continues to be expressed at the isthmus at later stages of development, where it serves to provide a guidance cue for the navigation of nearby axons. We are now studying the generality of Fgfs as chemotropic agents for axons in the brain and also in the olfactory system, in which defects in an FGF receptor underlie cases of human Kallmann's syndrome.

In addition, we have recently discovered that FGFs may also regulate aspects of synaptic plasticity and will be developing this theme in the future. same signal from the same source may serve to instruct several of these processes either simultaneously or sequentially. Moreover, we have found that the same signalling centre may serve to direct the development of tissues adjacent to the brain, thereby coordinating head development both spatially and temporally. We make use of three vertebrate model organisms in our work, zebrafish, chick and mouse, according to which is best-suited to address any particular question and we also utilise organ, explant and tissue culture approaches. Some ongoing projects are introduced below and further details can be found on the web page of individuals in our group.

Failure of neural tube closure (neurulation) is a major source of human birth defects, the most severe form being craniorachyschisis, in which closure fails to initiate in the midbrain resulting in a complete failure of brain closure. We are studying a transmembrane receptor called Flamingo which, when defective, results in craniorachyschisis in mammals and defective neurulation in zebrafish. Nothing is known about how Flamingo signals within the cell, how it is activated and in which cells it is required during neurulation. We are currently seeking to address all of these problems.

During and immediately after neurulation, local signaling imparts regional identity to the brain. We have examined this in detail in the context of Fgf8, which signals from the boundary between midbrain and anterior hindbrain (the isthmus) to specify and pattern those two structures. We also established the generality of this mechanism, identifying similar Fgf-producing signalling centres in both forebrain and hindbrain. Current work focuses on understanding the intracellular signalling pathways and their feedback inhibitors that mediate Fgf function particularly at the isthmus. We are also examining how cell fate and neural progenitor proliferation are regulated in these regions. Such studies have led us to investigate how the multiple signals that impinge on neural progenitors are integrated within the cell. We are studying this problem in the context of Fgf, Wnt, BMP/GDF and Shh signals.

We showed recently how Fgf8 continues to be expressed at the isthmus at later stages, where it serves to provide a guidance cue for the navigation of nearby axons. We are now studying the generality of Fgfs as chemotropic agents for axons in the brain and also in the olfactory system, in which defects in an FGF receptor underlie some cases of human Kallmann’s syndrome.