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Developmental biology - SOX Genes

Genes'Give Clues How New Cell Types Evolve

A family of essential gene interactions could offer clues to how new types of cells evolved...

Developmental biologists at the University of Bath in the United Kingdom, have new insight into how a family of essential genes affects interactions between cells. Their observations offer clues about how new cell types evolve based on how SOX genes affect the growth and development of zebrafish and medaka fish.

SOX genes are found in all mammals (including humans), reptiles, birds, fish and insects. They are known to be crucial in the development of brain cells, stem cells and in various specialized cell as they develop from precursor cells. Usually a precursor cell is a stem cell which has the capacity to differentiate into only one cell type.

There are around 20 SOX genes which code for proteins called SOX transcription factors. SOX transcription factors regulate when genes are switched on and off by attaching to DNA strands and controlling the activity of nearby genes. Uncovering how these genes function has important consequences for understanding how the body makes different cell-types, or how this system fails in disease. For example, SOX10 has long been associated with diseases in which melanocytes and neurons fail to be made, such as in Waardenburg Syndrome and in Hirschsprung Disease.
Waardenburg Syndrome

Waardenburg Syndrome can cause pigmentation changes in skin from patchy discoloration, locks of hair, and eye color changes affecting only one eye or both.

Researchers were interested in how SOX proteins interact as pigment cells develop in zebrafish with their three types of pigment cells: melanocytes, iridophores and xanthophores. Medaka fish have those three cell types plus the additional leucophores. All of these four cell types form important and often beautiful pigment patterns in fish scales. Two SOX proteins, encoded by the SOX10 and SOX5 genes, are involved in pigment cell development in both fish species.

Researchers found that in both species, SOX10 is essential to develop the three types of pigment cells they have in common, while SOX5 slightly down regulates the action of SOX10 on all three pigment cells melanocytes, iridophores and xanthophores in zebrafish. But, only for melanocytes and iridophores in medaka fish. In medaka fish both SOX10 and SOX5 work by co-operating to repress leucophore cells, which are chromatophores that show up white in reflected light, and promote the formation of xanthophores.

The work is published in PLOS Genetics.

Professor Robert Kelsh, research leader: "How individual cells become specific cell-types, from precursor cells that could become anything, is a fundamental question in developmental and stem cell biology. We have worked on SOX10 for a long-time, showing its important role in helping make many specialized cell-types. We began looking at the role for SOX5 because this gene has been shown to work with SOX10, but in different ways. Our research shows these transcription factors work in a context-specific way. In some cell-types they work together, in others SOX5 antagonises SOX10. For melanocytes this antagonism functions the same way as it does in mammals. But what really surprised us was how SOX5 and SOX10 interact in opposite ways to govern development of xanthophores.

"We see the same proteins are working together differently depending on the context - so what's happening? We suggest that this likely relates to the evolution of a novel pigment cell type - the reflective leucophore - in medaka.
"Our previous work had shown that at a genetic level we can consider the leucophore to be a xanthophore that has been modified to become reflective. We speculate that this may be intimately linked to the change in relationship between SOX5 and SOX10 in the formation of the xanthophore. But exactly why, and exactly how this works, we don't know - that is the next mystery for us to investigate!"

Robert Kelsh PhD, Professor, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.

Mechanisms generating diverse cell types from multipotent progenitors are fundamental for normal development. Pigment cells are derived from multipotent neural crest cells and their diversity in teleosts provides an excellent model for studying mechanisms controlling fate specification of distinct cell types. Zebrafish have three types of pigment cells (melanocytes, iridophores and xanthophores) while medaka have four (three shared with zebrafish, plus leucophores), raising questions about how conserved mechanisms of fate specification of each pigment cell type are in these fish. We have previously shown that the Sry-related transcription factor Sox10 is crucial for fate specification of pigment cells in zebrafish, and that Sox5 promotes xanthophores and represses leucophores in a shared xanthophore/leucophore progenitor in medaka. Employing TILLING, TALEN and CRISPR/Cas9 technologies, we generated medaka and zebrafish sox5 and sox10 mutants and conducted comparative analyses of their compound mutant phenotypes. We show that specification of all pigment cells, except leucophores, is dependent on Sox10. Loss of Sox5 in Sox10-defective fish partially rescued the formation of all pigment cells in zebrafish, and melanocytes and iridophores in medaka, suggesting that Sox5 represses Sox10-dependent formation of these pigment cells, similar to their interaction in mammalian melanocyte specification. In contrast, in medaka, loss of Sox10 acts cooperatively with Sox5, enhancing both xanthophore reduction and leucophore increase in sox5 mutants. Misexpression of Sox5 in the xanthophore/leucophore progenitors increased xanthophores and reduced leucophores in medaka. Thus, the mode of Sox5 function in xanthophore specification differs between medaka (promoting) and zebrafish (repressing), which is also the case in adult fish. Our findings reveal surprising diversity in even the mode of the interactions between Sox5 and Sox10 governing specification of pigment cell types in medaka and zebrafish, and suggest that this is related to the evolution of a fourth pigment cell type.

Yusuke Nagao, Hiroyuki Takada, Motohiro Miyadai, Tomoko Adachi, Ryoko Seki, Yasuhiro Kamei, Ikuyo Hara, Yoshihito Taniguchi, Kiyoshi Naruse, Masahiko Hibi, Robert N. Kelsh , Hisashi Hashimoto.

The authors thank M. Shedden, Y. Tsukazaki, K. Kondoh and Y. Takayanagi for fish care. Also, thanks to A. Gesell for help with confocal imaging. Dr. M. Kinoshita kindly provided us pCS2-hSpCas9. Dr. J. Wittbrodt kindly provided medaka Tg(hsp70:cre) fish. We are grateful to NBRP Medaka (https://shigen.nig.ac.jp/medaka/) for providing sox9bK136X TILLING mutant (Strain ID: MT830) and BAC clone (ola-008A15).

This research was, in part, supported by the National Cancer Institute's National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research. The researchers also received assistance from the Cleveland Center for Membrane and Structural Biology and Department of Ophthalmology and Visual Sciences (NIH Core Grant P30EY11373). The study was also supported by a National Institutes of Health grant (1R01GM108921), and Cryo-EM supplement (3R01GM108921-03S1) to S.C and the American Heart Association postdoctoral Fellowship to S.B (17POST33671152).

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Nov 8, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Leucophore formation does not require Sox10 function, but is repressed by Sox10 and Sox5 (A-H) 9 dpf. In these dorsal views of fish: Leucophores (ORANGE) - are distributed along the dorsal surface throughout the anterio-posterior axis - as scattered individual cells in the head, and along the midline in the body (A). As the number of functional sox10 alleles decreases, leucophore increase in number on the head (A-D, I, p<0.05 by Kruskal-Wallis test), whereas on the body, they are progressively decreased. Image Credit: Robert Kelsh et al.

Phospholid by Wikipedia