Stephen Gaunt

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Caudal (Cdx) and Hox proteins as regulators of the embryonic body plan

During the early development of a mouse or human embryo, the correct location of body parts along the head-to-tail axis is specified by the expression boundaries of 39 special genes known as Hox genes. These are differentially expressed along the embryo in a series of partially overlapping domains. Each Hox protein is expressed in a unique spatial domain along the body where, functioning as a transcription factor, it instructs embryonic cells on a particular route of morphogenesis. Hox expression domains thus provide a pre-pattern to the body plan. A central question in developmental biology is to understand how these domains are established. We have proposed that these form along instructional (morphogen) gradients of the three caudal proteins (Cdx1, Cdx2 and Cdx4), which are upstream activators of Hox genes.

Two predictions of the morphogen gradient theory are 1) that the Cdx proteins form concentration gradients along the embryonic axes, and 2) that Hox genes respond to Cdx proteins in a dose-dependent way. A major area of our research is to seek evidence for both of these predictions. We have shown how, in a novel mechanism, Cdx protein gradients form by a process of protein decay within cells that arise from the growth zone in the tailbud of the developing embryo.

A second area of our research is to elucidate the intracellular signalling pathways that regulate Cdx genes both within the embryo and also at another site of their activity, the gut.  Cdx1 in embryos is regulated by retinoic acid and Wnt3a. Our findings have indicated how acquisition of new regulatory elements for these signals may have facilitated the morphological evolution of new vertebrate groups. We also elucidated how Cdx2 in gut cancer cells is regulated by ERK1/2 signalling. A major part of our current work is aimed at study of Hox and Cdx regulation in mouse embryo stem cells. One objective here is to test how far such an in vitro system can provide a satisfactory replacement for similar studies that utilize animals.