News / 16 September 2020

Keratins – best known as the main structural component of hair and nails – play a crucial role in the early stages of mammalian development, research by an EMBL Australia group leader and his colleagues has revealed.

Published in leading journal Nature, the international collaboration led by EMBL Australia alumnus Dr Nicolas Plachta and including group leader Dr Maté Biro (based at UNSW’s Single Molecule Science), has uncovered the surprising role of a protein, keratin, in determining cell fate in the earliest stages after fertilisation.

Dr Biro said the discovery, using advanced live mouse and fixed human embryo imaging, brings us one step closer to answering the question that is essentially a ‘holy grail’ of the developmental field.

“We all know that an egg and sperm fuse into one cell, that then starts to divide. The really fundamental question is how do you go from one cell to a complex multicellular organism where the downstream cells have fate (some cells will become bone, some skin, some brain and so forth)?” Dr Biro said.

“That’s obviously a very difficult thing to imagine when you draw the line from a single cell all the way to a complex human adult, but even in the very earliest stages of embryo development (just after the first few divisions) there is fate specification.”

Dr Biro said it was known there was fate specification at the stage where a cell has divided to become 16 cells – cells that stay at the outer edge (or trophectoderm) of the embryo later form the placenta, those that end up inside the embryo form the foetus – but the question remained unanswered as to how these fates are determined.

“What was known was that the positioning of the cell was linked to fate (inner and outer cells had a certain fate), but how this is achieved is currently intensely studied,” he said.

There are three main components of the cellular cytoskeleton: actin, microtubules and a class of filament called intermediate filament, which keratins form part of.

Dr Biro said that the function of keratins – the main component of harder tissues like hair and nails – in early development was almost entirely unknown.

“It has long been known that keratins show some heterogeneity in these early embryos but no one knew why, so we followed that up and found out that they are actually determining the eventual fate of cells,” he said.

Dr Biro said this research reveals that there are asymmetric divisions (when a single cell divides into two daughter cells with distinct properties and identities) at this early stage, and that the difference between the sibling cells was the way they inherit these keratin filaments.

“In very simple terms, the outer layer that inherits keratin basically forms the placenta and the inner cell mass (which inherits very few keratin filaments, if any at all) will form the foetus,” Dr Biro said.

“These keratin filaments, because they are a structural component, confer mechanical properties to the cells as well.”

Dr Biro said this work builds upon research he and his collaborators previously published in Cell that showed that networks or rings of actin – another cytoskeleton component – only appear at the outermost cells. He said these keratin filaments are linked to the actin networks and stabilise the rings.

“The difference is that we previously showed the actin proteins are inherited symmetrically because any kind of ring structure is disassembled during division, ensuring that that structural component is inherited equally. But keratins, on the other hand, are not,” Dr Biro said.

“So, this is really the first discovery in early mammalian embryos of an asymmetrically inherited fate determinant – the cells that will inherit these keratins are the ones that will become the placenta.”

Dr Biro said the research was a result of a longstanding collaboration between himself and Dr Plachta, a former EMBL Australia group leader now based at the University of Pennsylvania.

He said the pair worked on these early embryo developmental questions by combining their respective areas of expertise, with Dr Plachta being a world-leading expert in imaging the dynamic processes that happen during divisions and the development of the early embryo and Dr Biro bringing expertise in mechanobiology and cytoskeletal dynamics.

Dr Biro said, having researched actin rings and keratins, and Dr Plachta having previously worked on microtubules (the third main class of filament in the cytoskeleton) in the context of early embryo development, the next step will be to combine the findings.

“We want to come full circle and build an integrated model where all of these three classes of cytoskeletal filaments are mapped in terms of their role in fate determination and early embryo development,” he said.

For a more detailed explanation of this work, see this Nature ‘News and Views’ article.

Access the Nature paper here.

Lim, H.Y.G., Alvarez, Y.D., Gasnier, M. et al. Keratins are asymmetrically inherited fate determinants in the mammalian embryo. Nature (2020). https://doi.org/10.1038/s41586-020-2647-4