In Development this week (Vol. 143, Issue 24)

Here are the highlights from the new issue of Development…the last one of the year!

SETting chromatin state through transcription

Setd5 is a poorly characterised murine member of the SET domain family, generally associated with histone methyltransferase activity. However, the closest homologues of Setd5 are thought to be catalytically inactive, and have instead been associated with the regulation of histone acetylation levels at genes. On p. 4595, Anna Osipovich and colleagues generate Setd5 mutant mice and embryonic stem cells (mESCs). Setd5 homozygosity is lethal, with mutant embryos failing to survive beyond E10.5. Phenotypically, mutants display multiple defects, most notably in the cardiovascular system. Globally, cell proliferation is impaired and apoptosis increased. The mESC system reveals phenotypes consistent with the in vivo observations, including impaired differentiation down the cardiac lineage, while RNA-seq analysis shows that over 10% of coding genes are dysregulated in mutant cells – including key genes involved in cardiovascular development. Setd5 interacts with members of the polymerase-associated factor 1 complex (PAF1C) and NCoR co-repressor complex, the latter of which mediates gene silencing through histone deacetylation. Although the precise developmental consequences of Setd5 ablation have yet to be fully understood, this work suggests that this protein might cooperate with PAF1C and NCoR to mediate co-transcriptional regulation of histone acetylation and gene activity.

A new view on implantation

Implantation of the blastocyst into the uterus is obviously a critical step in mammalian development, yet we understand very little about the three-dimensional environment into which the embryo implants. It is known that, in mouse at least, blastocysts attach in uterine crypts, but how these form and whether such structures are also found in human is unclear. Here (p. 4749), Diana Laird and colleagues seek to provide new insights into uterine architecture before, during and after implantation. The authors develop sophisticated imaging and computational tools to characterise the 3D structure of the mouse uterine luminal and glandular epithelium, showing that the pattern of folding alters dramatically prior to implantation, giving rise to folds that overlap with structures described as crypts. Moreover, uterine glands reorient towards the site of implantation and show structural changes. This technology is able to detect architectural defects in mutant animals (such as aberrant luminal folding in Wnt5a mutants) and can also be applied to human uterus samples – as well as, potentially, other organs. This work provides an unprecedented view of the environment into which the embryo implants, and opens up avenues for further analysis of the mechanisms underlying uterine restructuring during early pregnancy.

Sparking regeneration with ROS

During regeneration, multiple signalling pathways act to coordinate the various processes required to regenerate an injured organ or body part. Both reactive oxygen species (ROS) and electric currents have been shown to modulate regeneration, but how they exert their effects, and whether their activities might intersect, is poorly understood. Here (p. 4582), Fernando Ferreira, Min Zhao and colleagues set out to address the potential interplay between ROS and bioelectric phenomena using the Xenopustadpole tail regeneration model. They uncover a dual role for NADPH oxidases in regulating bioelectric activities: NADPH oxidase-driven electron flow induces membrane depolarisation, while the hydrogen peroxide produced leads to activation of sodium channels in cell membranes of the regeneration bud, with consequent effects on transepithelial potential and electric currents that mediate regeneration. Moreover, external application of hydrogen peroxide can induce tail regeneration during the refractory period in the tadpole’s life – when regeneration is normally blocked – as well as the formation of ectopic tails at injury sites during the regenerative period. Although the mechanisms by which bioelectric activities might modulate the cellular processes required for regeneration still require further investigation, this work links two previously unconnected regulators of regeneration and provides convincing evidence for redox-bioelectric integration in this context.

Robust transcriptional control of multiciliogenesis

Multiciliated cells (MCCs) are found on various epithelia where they drive fluid flow – such as in the airways, the brain ventricles, and the skin of Xenopus embryos. Their differentiation is known to be coordinated by transcriptional regulators such as Multicilin and Gemc1, as well as by the key transcription factor Foxj1, which is also required for cilium formation in cells that produce just a single motile cilium. On p. 4654, Chris Kintner and colleagues identify another transcription factor required for proper differentiation of MCCs – Foxn4. Through an elegant combination of morpholino and CRISPR-based loss-of-function technologies, they show that loss of foxn4 disrupts docking of basal bodies to the cell surface – an essential prerequisite for cilium extension. This phenotype is reminiscent of the foxj1 phenotype, except that it largely recovers over time and that foxn4 has no apparent effect on cells with a single cilium. Through RNAseq and ChIPseq analyses, the authors find that Foxn4 promotes expression of a subset of Foxj1 targets. They propose that Foxn4, acting downstream of Multicilin, might be required to promote high-level expression of Foxj1 target genes that may be necessary for efficient generation of multiple cilia.

PLUS

An interview with Doug Melton

Doug Melton is Xander University Professor at Harvard University, co-director of the Harvard Stem Cell Institute and a Howard Hughes Medical Institute Investigator. His lab investigates the development of the pancreas, and uses insights from this process to direct the production of insulin-producing beta cells from stem cells. We met Doug at the 2016 Society for Developmental Biology-International Society of Differentiation (SDB-ISD) joint meeting in Boston, USA, where he gave the Jean Brachet Lecture. See the Spotlight article.

Fox transcription factors: from development to disease

Forkhead box (Fox) transcription factors regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In their Primer, Maria Golson and Klaus Kaestner review these studies and provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development.

The many faces of hematopoietic stem cell heterogeneity

Not all hematopoietic stem cells (HSCs) are alike: they differ in their physical characteristics, they respond to different extrinsic signals, and they have different lineage outputs following transplantation. This  raises questions as to why HSC subtypes exist, how they are generated, and whether HSC heterogeneity affects leukemogenesis or treatment options. In their Review, Mihaela Crisan and Elaine Dzierzak provide a developmental overview of HSC subtypes during embryonic, fetal and adult stages of hematopoiesis and discusses the possible origins and consequences of HSC heterogeneity.

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