Publication highlights

Cells need to be made in the right place at the right time in developing tissue, but how these two cues are coordinated to control cell identify is not well understood. Using mouse stem cell models of the neural tube, researchers at the Crick found a surprising "master clock" mechanism that modifies the chromatin of neural cells, making different DNA regions accessible at specific times during development. Working with the High Throughput Screening team, they identified key molecular regulators, including a transcription factor called Nr6a1, that control the temporal programme by altering chromatin accessibility. Disrupting these factors altered the identity of cells before and after becoming specialised. The ability of temporal factors in the mice to control chromatin accessibility over time explains how the same spatial progenitor domains can produce different cell types as development progresses. Taking into account the cell’s temporal clock could help engineer the generation of specific neurons and glial cells from stem cells for regenerative medicine purposes.

The Stem Cell Biology and Developmental Genetics Laboratory at the Crick has shown that in a mouse model of human hypopituitarism, low doses of aspirin and the balance of bacteria in the gut can influence symptoms. The brains of these mice, which lack the Sox3 gene, had a reduced number of a hypothalamic cell type, NG2 glial cells. Treating Sox3-deficient animals with a low dose of aspirin for 21 days increased NG2 glia numbers and reversed the hypopituitarism, but highly surprisingly, the makeup of the gut microbiome also had a significant effect; the change in microbiome resulting from the mice migrating into the Crick animal facility from elsewhere was enough to rescue the hormonal deficiencies. In addition to providing a clear case where extrinsic factors can influence a robust phenotype caused by a mutation, the work has implications for experimental consistency between research facilities, and has garnered wide interest in the field.

Researchers at the Francis Crick Institute have shed light on the proteins controlling the development of ovaries in mice before and after birth. They found that a protein called FOXL2, which sits on top of specific regions in DNA ('enhancers') and influences whether and how other target genes are read, plays a role during embryonic development, but has the most impact after birth. Using chromatic proteomics to fish out' all of the other proteins that interact with FOXL2 when bound to DNA, they found that a number of protein interactions drastically increased in ovaries after birth. They believe another protein called USP7 is needed to stabilise FOXL2 on top of DNA as removing the Usp7 gene from female mice made them infertile. As FOXL2 and USP7 share some common roles in humans, this research could inform causes of female infertility.

Researchers at the Francis Crick Institute and the Université Cote d’Azur, together with other labs in France and Switzerland, have identified a gene which is an early determining factor of ovary development in mice. The team investigated the role of a gene, Wt1, in sex development in mice. They found that one form of the WT1 protein (-KTS) was essential to gonad formation, as in its absence, neither Sertoli cells nor granulosa cells could form in both XY and XX mice. They then looked at mice where Wt1 was mutated to only make the -KTS form of the protein. Here the researchers saw that twice as much -KTS was produced to compensate for the lack of other forms of the protein. The higher amounts of -KTS reduced the expression of Sry in XY gonads and increased genes involved in ovarian development. The production of SRY never reached the level needed to trigger testes development.

This systematic study revealed the complexity of the Sox9 regulatory region, but just one enhancer, “Enh13”, was shown by mutation studies to be essential for testis and subsequent male development. Sox9 expression is at the same very low level in XY Enh13 mutant embryos as in control XX gonads. Enh13 is efficiently bound by Sry in vivo and functions to initiate Sertoli cell fate during a short time window. This is in contrast to other redundant enhancers (e.g. TES) that bind Sry, but act later. This study helped explain Disorders of Sex Differentiation (DSDs), due to deletions and duplications mapping far upstream of Sox9, where the human Enh13 equivalent is located, as well as showing that some enhancers can be pioneering rather than redundant.