From frogspawn to frog: understanding how organisms develop

Two-headed frog embryo with over-expressed PAWS1 (left) compared with a non-modified frog (right).

Two-headed frog embryo with over-expressed PAWS1 (left) compared with a non-modified frog (right).

- Credit: Kevin Dingwell, Francis Crick Institute

Why are some scientists at the Crick so interested in frogs? Scientists at the Crick are dedicated to understanding the biology underlying human health and disease, and lots of them use specific animal species, known as model organisms. These help us to understand processes and mechanisms that are fundamental to human biology.

For example, we know lots about the mechanisms of early development in vertebrates from research using the African clawed frog (Xenopus laevis) and Western clawed frog (Xenopus tropicalis).

Xenopus are easy to breed and keep, they don't take up too much space, they can mate frequently, and they lay thousands of robust eggs which are easy to develop and observe ­- all of this makes them an excellent model for studying how organisms develop.

Jim Smith's Developmental Biology Lab at the Crick have recently uncovered two new insights into development in Xenopus frogs, deepening our understanding of the mechanisms that support this crucial process.

Two-headed frogs and human disease

Researchers at the Crick and Dundee University have demonstrated a significant role for a protein called PAWS1 in controlling a mechanism associated with a range of diseases and defects. This mechanism is called Wnt signalling, and it is essential for passing signals into cells.

To investigate PAWS1, the scientists over-expressed the protein in early Xenopus embryos. To their surprise, this induced the formation of embryos with two well-formed heads, a response typically observed after activating Wnt signalling. Following this observation, the scientists were able to confirm that, in both Xenopus embryos and in human bone cancer cells, PAWS1 regulates Wnt signalling.

Using mass spectrometry techniques, they were then able to work out how PAWS1 controls Wnt signalling, which could help scientists to boost or disrupt this mechanism in future.

Abnormal Wnt signalling is associated with many cancers, particularly colorectal cancers. This new understanding of how PAWS1 regulates Wnt signalling may provide new opportunities and targets for effective therapies.

Jim Smith said, "Although the precise function of PAWS1 was poorly understood, PAWS1 mutations are known to cause palmoplantar hyperkeratosis, a disease in which there is excessive skin cell growth on the soles and palms and can affect normal hair growth leading to conditions such as alopecia.

"Wnt signalling is known to play crucial roles in the maintenance of skin tissue and hair development. Our findings that PAWS1 is an important player in Wnt signalling now offer an opportunity to establish whether the pathogenic PAWS1 mutations impact Wnt signalling to give rise to this disease."

"This research is an outcome of a long-standing collaboration between the Dundee and Crick labs. It represents a wonderful example of how collaboration facilitates key scientific discoveries."

The findings are published in EMBO Reports. Dr Kevin Dingwell, from Dr Smith's lab, and Polyxeni Bozatzi, a PhD student in Dr Sapkota's lab at Dundee, and are joint lead authors of this study.

One, two, four, eight, sixteen: a frog's first 12 cell divisions

The embryos on the left and right hand column are control embryos, and those in the middle have had xNuRD deactivated.

In another study, published in Cell Reports, the lab identified a protein complex that is essential for DNA replication during early Xenopus embryo development, before a key transition.

The mid-blastula transition is a significant moment in Xenopus embryo development. Before the transition, cell division in the embryo is faster, regular and synchronised, with DNA replication initiating at random sites in the genome. The transition happens after 12 rounds of cell division, after which cell division becomes slower, cells begin to organise and move around, and DNA replication initiates at defined points on the genome. At this stage, replication is dependent on small non-coding Y RNAs.

The team discovered that a protein complex called xNuRD is essential for DNA replication before the transition, without any non-coding Y RNAs. They show that when xNuRD is deactivated in the Xenopus embryo, the embryo fails to develop and dies.

The paper is also the result of a collaboration, between Jim Smith's lab at the Crick, Dr Torsten Krude's lab at the University of Cambridge and the MRC Laboratory of Molecular Biology. Dr Kevin Dingwell (Crick) and Dr Christo Christov (Cambridge) are the lead authors.

Jim Smith is Director of Science at Wellcome, but made his contribution to these papers as part of his role as a visiting Group Leader at the Crick. Wellcome had no role in the writing or decision to submit these papers for publication, except for the involvement of Jim Smith as a contributing author.

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