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Mucosal melanoma (MM) is a cancer with poor prognosis derived from mucosal melanocytes. Here, the authors implement a combination of genetic changes that occur in MM patients in a zebrafish model, revealing the potential MM cell of origin and showing that patient and zebrafish MMs share a gene signature that is more metastatic and immune-evasive.

Here they show that ATF7IP/SETDB1-mediated epigenetic programming governs T lymphoid progenitor trafficking and differentiation, providing important insights into the pathogenesis of human T lymphoid diseases.

The proliferation and differentiation of hematopoietic stem cells is regulated by BMP-4 and Shh. These factors collaborate with cytokines in the bone marrow to create an environment that maintains stem cell homeostasis

In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.

Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes.

An in vivo imaging-based competitive transplant screen in zebrafish identifies epoxyeicosatrienoic acids as enhancers of haematopoietic stem and progenitor cell (HSPC) engraftment; these derivatives of arachidonic acid also promote zebrafish developmental HSPC specification through a PI(3)K-dependent AP-1 and runx1 transcriptional program and their pro-engraftment effect is conserved in mammals (indicating clinical potential).

Scientific society seeks smart growth

The zebrafish has emerged as an important model system with which to investigate cancer, particularly for validating genomics data and for undertaking screens for oncogenes and drivers of tumour progression and metastasis. This Review outlines what we have learned and could still learn from cancer research using the zebrafish.

Enhancer variants associated with red blood cell traits alter signaling transcription factor motifs, leading to changes in expression of genes that are upregulated during erythroid differentiation.

A platform for automated screening of zebrafish larvae in high throughput should allow detection of phenotypic changes in single cells.

Blood cells are generated from haematopoietic stem cells on demand. The protein Lkb1, which lies at the crossroad of energy metabolism and cell growth, seems to regulate these stem cells' dynamics. See Articles p.653, p.659 & Letter p.701

Knowing how an organism's tissues handle stress throughout life is key to understanding ageing and disease. Stems cells of the blood system seem to tackle metabolic stress by means of a process called autophagy. See Article p.323

Different cell types produce signals that regulate the activity of blood-forming stem cells. A study shows that certain rare mesenchymal cells surrounding blood vessels are the main source of one such signal in mice. See Article p.457

Zon and colleagues have performed a reverse genetic screen to target orthologues of 425 human chromatin factors in zebrafish. This allowed them to delineate chromatin regulators that function at distinct stages of primitive and definitive blood formation.

Loss of NECTIN1 is a frequent event in human melanoma and is associated with metastasis. NECTIN1 depletion modulates a switch from cell–cell adhesion to cell–matrix adhesion in response to low levels of IGF1 signaling from the microenvironment.

The heart forms from combining the first with the second heart field, which in mammals creates left and right ventricle. Here transgenic zebrafish and physiology studies reveal that transcription factors controlling septation in mammals already in teleosts guide muscle coupling by controlling the relative contribution of the two fields to the heart.

This study identifies Prostaglandin E2 (PGE2) as an important modulator of vertebrate haematopoietic stem cell (HSC) number. Chemicals that enhance PGE2 synthesis increase the number of HSCs whereas the opposite effect is achieved by blocking PGE2 synthesis.

Stress induces hair greying in mice through depletion of melanocyte stem cells, which is mediated by the activation of sympathetic nerves rather than through immune attack or adrenal stress hormones.

Zebrafish are useful model organisms for drug discovery, particularly in screening, disease modelling and toxicity assays. Here, Patton, Zon and Langenau discuss key recent successes in which zebrafish models have had key roles. Advances in gene modification technologies have enabled individual mutations to be recapitulated in zebrafish, leading to individualized treatments. Zebrafish xenografts as cancer models could also lead to rapid, personalized platforms for drug discovery.

The telomerase reverse transcriptase promotes the development of haematopoietic cells in zebrafish independent of its telomere-lengthening activity. Here Alcaraz-Pérez et al.show that the telomerase RNA component regulates cell fate during zebrafish myelopoiesis also in a non-canonical manner.

Henninger et al. analyse the early clonal events that underlie haematopoiesis and establish the number of stem cell clones that arise from the ventral dorsal aorta to maintain lifelong blood production.

There are more than 20 known melanoma susceptibility genes. Here, using a massively parallel reporter assay, the authors identify risk-associated variants that alter gene transcription, and demonstrate that expression of one such gene, MX2, leads to the promotion of melanoma in a zebrafish model.

TCR ligation activates the tyrosine kinase ZAP-70 to phosphorylate the adapter LAT, which then coordinates TCR proximal signaling cascades. Weiss and colleagues show LAT-Y132 is critical to TCR ligand discrimination, as its phosphorylation represents a rate-limiting step in T cell activation due to a conserved glycine residue at position 131.

Human brain structure changes throughout the lifespan. Brouwer et al. identified genetic variants that affect rates of brain growth and atrophy. The genes are linked to early brain development and neurodegeneration and suggest involvement of metabolic processes.