Hox gene, Wnt and chemokine receptor expression in directional cell migration

02 October 2013

Research by scientists from NIMR has shown that a Hox gene regulates collective cell migration by regulation of chemokine receptors. The work is published in the Proceedings of the National Academy of Sciences, USA.

Collective cell migration, in which cells move as a coherent group with front and rear polarity, is important both during embryo development and tumour cell metastasis. Key mechanisms underlying collective migration have been uncovered using the lateral line primordium in zebrafish as a model. Previous work has shown that Wnt signaling leads to polarised expression of two chemokine receptors – cxcr4b and cxcr7b - which are essential for directional migration of the primordium along a track of Sdf1a chemokine.

In this study, Marie Breau, David Wilkinson and Qiling Xu (pictured), from NIMR’s Division of Developmental Neurobiology, uncover a critical role of a homeobox gene. They show that hoxb8a acts downstream of the Wnt pathway to coordinate the expression of both chemokine receptors. This involves a network of regulatory interactions in which Hoxb8a expression is induced by and cooperates with Wnt signalling to up-regulate cxcr4b, and acts through multiple mechanisms to repress cxcr7b expression.

“Our results provide the first evidence that a Hox gene controls migration of the lateral line primordium, in which it functions downstream of the Wnt pathway to regulate chemokine receptors. This network couples signalling, patterning and migration. It is tempting to speculate that a Wnt-Hox-chemokine receptor network functions in other tissues or pathological conditions, where so far only two of the three components have been implicated. Cancer stem cell mobilisation and tumour metastasis require concerted changes in cell signalling and cell migration.

It is intriguing that Wnt signalling, Hox proteins and chemokine receptors have all been implicated in tumour progression, such as the aggressive forms of leukemia bearing Mixed-Lineage Leukemia translocation. The regulatory network we have uncovered in the lateral line migration points to the importance of dissecting out the relationship among Wnt, Hox and chemokine receptors in order to better understand the etiology of cancers and find better therapeutic targets.

Qiling Xu

Click image to view at full-size

hoxb8a is expressed in the leading part of the primordium (A) and primordium migration is retarded in hoxb8a morphant embryo (B).

Original article

Marie A. Breau, David G. Wilkinson, and Qiling Xu (2013)

A Hox gene controls lateral line cell migration by regulating chemokine receptor expression downstream of Wnt signaling

Proceedings of the National Academy of Sciences, USA. Epub ahead of print. Publisher abstract

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