Publication highlights

Researchers at the Crick and the University of Pittsburgh have used x-ray crystallography and cryo-electron microscopy to determine the structures of betaglycan - a co-receptor involved in cell signalling - in complex with the TGF-β protein and its signalling receptors. They found that both domains in betaglycan are involved in ligand binding, demonstrated how this occurs, and revealed that their arrangement also allows for signalling receptor recruitment. The results provide a structural explanation for how betaglycan functions to capture the ligand and hand it over to the receptors in a sequential manner, to selectively enhance TGF-β signalling.

Tissue development and homeostasis require coordinated communication, proliferation, and movement of cells on a grand scale. Erk is a key protein connecting these processes downstream of many signals. Depending on the signal, different Erk dynamics can be achieved that drive different cell behaviours. Researchers at the Crick wanted to investigate the role of Fgf/Erk signalling during early development using a live biosensor, called the Erk Kinase Translocation Reporter (Erk-KTR), but found that the readout was masked by off-target activity of another protein called Cdk1, a particular problem during rapid embryonic cell cycles. They therefore generated an improved Erk-specific KTR (modErk-KTR) and demonstrated its Erk-specificity in vitro and in multiple zebrafish and Drosophila tissues.

Using this tool, the researchers tracked the growth of the Fgf/Erk signalling gradient in zebrafish early embryos. In a type of cell called a mesendodermal cell, they saw that Erk activity is rapidly stopped before mitosis (cell replication). The two daughter cells reactivate Erk signalling once mitosis is complete. They conclude that mitosis creates variable pulses of Erk inactivity – called ‘mitotic erasure’ – during a key window of embryo development.

How complex organisms are constructed from far simpler embryos is a central problem of biology. During embryonic development, pluripotent cells are guided to a variety of cell fates by a series of decision-making processes involving gradients of chemical and mechanical signals. A concentration gradient of the Nodal protein has long been thought to specify endodermal and mesodermal cell fates, depending on how much Nodal a cell is exposed to. However, this model is too simple, as neighbouring cells in the embryo can adopt different fates despite being exposed to similar concentrations of Nodal. The Hill lab has demonstrated that rather than pushing cells down a particular path, a gradient of Nodal signalling establishes a window of competency in which cells can switch to an endodermal fate. Those that don’t switch become mesoderm. Switching is a random event, the likelihood of which is modulated by signalling from another protein, Fgf. This imprecise mechanism is honed at later stages to produce clearly defined endoderm.