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New research by the Sauka-Spengler group unravels FoxD3’s dual role in a crucial process in embryonic development

Zebrafish embryos showing the expression of neural crest markers in the absence (left) or presence (right) of FoxD3

An essential group of cells

Majority of the bone and cartilage elements in our skull and face, the pigment cells in our skin, and neurons and glial cells in the periphery of our nervous system are all formed from a unique population of cells in the developing embryo called the neural crest cells. The neural crest is stem-cell-like population of cells crucial for the development of a healthy baby, and errors in their formation, or their later specialisation, are some of the most common causes of birth anomalies. These emblematic cells originally form close to the developing nervous system, but then segregate from it and migrate extensively into distant parts of the embryo to form diverse derivative structures.

In their latest paper in Developmental Cell, the group of Prof Sauka-Spengler teases out the role of the regulatory protein FoxD3, one of the key players in the formation and function of these cells.


Dual role

FoxD3© Erdinc SezginIn the beginning of embryo development all cells are identical, but over time a complex network of regulators gradually turns on and off genes in specific cell subsets. This allows cells to become increasingly specialised to perform different functions in different parts of the body. FoxD3 is one of these regulatory proteins, and is well known to play a role in the very early stages of development.

In their new paper, the Sauka-Spengler group shows that FoxD3 is also an important regulator in neural crest cells. To uncover this, the researchers compared which genes are turned on and off (the transcriptome) in normal cells and cells lacking FoxD3. The studies were performed using zebrafish embryos, a well-established model to study how embryos develop, due to its fast development time and embryo transparency.

Their analysis showed that FoxD3 plays two quite distinct roles in the neural crest. In the beginning, when cells are first acquiring their unique identity as neural crest, FoxD3 turns on a variety of important genes. Later on, as the neural crest cells are starting to specialise into different cell types, FoxD3 does the opposite, and is able to turn genes off.


Opening and closing

The team was able to dig deeper and uncover the mechanism for this dual action. DNA in cells is folded into compact domains called chromatin. This allows for the 2 meters of DNA to be able to be packed into each cell, but it is also a way to regulate genes. For a gene to be turned on, chromatin has to become looser, allowing regulatory proteins to bind to the correct regions of the DNA. The team was able to show that FoxD3 has a ‘pioneer’ effect at the beginning of neural crest development - it is one of the first regulators that approaches the chromatin, being able to loosen the DNA so that other regulators can bind to it. In later stages of neural crest development, FoxD3 has the opposite effect, making chromatin more compact and less accessible. The researchers were also able to identify which other proteins must bind to FoxD3 to allow it to do both of its activities (and to switch between them).

This work establishes FoxD3 as an essential regulator of neural crest development. It paves the way for a better understanding of how the neural crest is specified and how it specialises into various tissues during embryo development.