Here are the highlights from the current issue of Development:

 

One-step transdifferentiation

Terminally differentiated cells are generally considered to be in a developmentally locked state in vivo; they are incapable of being directly reprogrammed into an entirely different state. Now, on p. 4844, Joel Rothman and co-workers show that the expression of a single transcription factor can trigger the transdifferentiation of fully differentiated, highly specialised cells in C. elegans larvae and adults. They show that brief ectopic expression of ELT-7, a GATA transcription factor that regulates intestinal differentiation, can specifically convert non-endodermal cells of the pharynx into fully differentiated intestinal cells. This conversion is accompanied by an increase in the expression of intestine-specific genes and a concomitant decrease in the expression of pharynx-specific markers and structural proteins. The reprogrammed cells also exhibit morphological characteristics of intestinal cells. These, together with other findings in the study, demonstrate that terminally differentiated cells can be reprogrammed to an alternative fate without the need for cell division, without the requirement for a dedifferentiated intermediate state and without prior removal of an inhibitory factor.

 

Stem cells and regeneration in a new light

Zebrafish have a remarkable capacity to regenerate and, as such, are being used increasingly to study stem cells and organ regeneration. Here, Chen-Hui Chen, Kenneth Poss and colleagues establish a luciferase-based approach for visualising stem cells and regeneration in adult zebrafish (p. 4988). The researchers generate several transgenic lines that enable ubiquitous or tissue-specific expression of both firefly luciferase and mCherry. They show that, unlike the fluorescence signal, bioluminescence in these lines, which they term zebraflash, readily penetrates through adult tissues and can easily be detected. Using the cardiac zebraflash line, they demonstrate that this approach can be used to monitor the extent of heart injury and subsequent regeneration in animals in a non-invasive and high-throughput manner. Furthermore, they report, this approach can be used to detect quantitatively the progeny of engrafted stem cells in recipient animals at high spatial resolution. This methodology, along with the transgenic lines presented here, offer a valuable resource for the study of stem cells and regeneration.

 

Rocking the Wnt pathway

Wnt signalling plays important roles during embryonic patterning and in tissue homeostasis, and mutations that affect the Wnt pathway are associated with cancer. Despite this, the exact way in which the Wnt pathway is regulated is still not fully understood. Now, Amy Bejsovec and colleagues uncover a novel regulator of Wnt signalling (p. 4937). Previous studies have shown that the Drosophila RhoGEF Pebble (Pbl) might influence patterning mediated by Wingless (Wg), the primary fly Wnt. Following this, the authors show that both loss- and gain-of-function Drosophila pbl mutants exhibit defects that are consistent with a role for Pbl in negatively regulating the Wg pathway. Furthermore, both Pbl and ECT2, the human homologue of Pbl, downregulate Wnt reporter activity in cultured Drosophila and human cells, highlighting a role for ECT2 as a potential proto-oncogene. Finally, the researchers show that, unlike most negative regulators of the Wnt pathway, Pbl acts downstream of Armadillo/β-catenin and may act through Rho1 to negatively regulate Wnt/Wg signalling.

 

Opening a passage for hair growth

The hair follicle epithelium forms a tube-like structure that is continuous with the epidermis, but how the lumen of this structure is created during morphogenesis and regeneration remains unclear. Now, Sunny Wong and colleagues identify a novel population of cells that initiates hair follicle lumen formation in mice (p. 4870). The researchers first provide a detailed characterisation of the infundibulum, the region encompassing the hair follicle mouth, and identify a population of keratin 79 (K79)-positive epithelial cells within this region. Using lineage tracing, they show that these cells are specified early during hair follicle development and migrate outwards from the hair germ into the epidermis prior to lumen formation. This migratory event is also observed during regeneration of the hair follicle; K79-positive cells are specified in the secondary hair germ and migrate out, eventually forming a continuous layer with pre-existing K79-positive cells. These findings identify both a novel mode of epithelial tube morphogenesis and a unique population of cells that migrate throughout the life cycle of the hair follicle.

 

Insm1 controls pituitary endocrine cell development

The pituitary gland is an endocrine organ that plays a role in various physiological processes, including growth, metabolism and reproduction. The development of various pituitary endocrine cells is influenced by a number of transcription factors and signals. In this issue (p. 4947), Carmen Birchmeier and colleagues report that the transcription factor Insm1 controls the differentiation of all endocrine cells in the mouse pituitary. The researchers show that Insm1 is expressed in pituitary progenitors and continues to be expressed in differentiated endocrine cells. Using Insm1 knockout mice, they demonstrate that Insm1 controls a pan-endocrine differentiation programme; genes encoding pituitary hormones or proteins involved in hormone production and secretion are downregulated in Insm1 mutant pituitary glands. By contrast, Notch signalling components and skeletal muscle-specific genes are upregulated, suggesting that Insm1 also represses inappropriate gene expression programmes in the pituitary. Finally, the researchers show that the SNAG domain of Insm1 is required for its function, acting to recruit histone-modifying proteins and transcriptional regulators.

 

Split thoughts on the neural crest

The neural crest (NC) is a transient structure that gives rise to multiple lineages. Despite intense studies, it is still unclear whether the NC represents a homogeneous population of cells. Here, Jean Paul Thiery and colleagues examine this issue (p. 4890). The authors first characterise the cranial neural fold in chick and mouse embryos and show that, prior to delamination, it contains two phenotypically distinct domains: neural ectoderm and non-neural ectoderm. The researchers then show that the two domains display temporally distinct delamination patterns. Cells specifically within the non-neural ectoderm are the first to delaminate, whereas a second population of delaminating cells then originates from the neural ectoderm in both chick and mouse embryos. Importantly, they report, cells within the two domains have distinct fates: those from the non-neural ectoderm give rise to ectomesenchymal derivatives, whereas those within the neural ectoderm give rise to neuronal derivatives. These, together with other findings, prompt the authors to revisit current definitions of the NC and the origin of ectomesenchyme.

 

PLUS…

 

Mechanisms of scaling in pattern formation

Many organisms and their constituent tissues and organs vary substantially in size but differ little in morphology; they appear to be scaled versions of a common template or pattern. Here, David Umulis and Hans Othmer investigate the underlying principles needed for understanding the mechanisms that can produce scale invariance in spatial pattern formation and discuss examples of systems that scale during development. See the Review article on p. 4830

Conveying principles of embryonic development by metaphors from daily life

How can the revolution in our understanding of embryonic development and stem cells be conveyed to the general public? Here, Ben-Zion Shilo presents a photographic approach to highlight scientific concepts of pattern formation using metaphors from daily life, displaying pairs of images of embryonic development and the corresponding human analogy. See the Spotlight article on p. 4827

 

 

 

 

Here are the highlights from the new issue of Development:

 

Broken-hearted over Hippo

Mammalian cardiac regeneration is greatly impeded by the massive loss of cardiomyocytes that occurs following acute injury. The failure of the remaining cells to proliferate is a considerable challenge for the field, but the molecular mechanisms that control cardiomyocyte proliferation in the adult heart are largely unknown. Now, on p. 4683, James Martin and colleagues demonstrate a role for Hippo signalling in suppressing adult and postnatal murine cardiomyocyte proliferation. Using conditional knockouts, the authors show that removal of Hippo pathway members Salv or Lats1 and Lats2 from normal adult cardiomyocytes results in increased proliferation, as these cells are able to re-enter the cell cycle and undergo cytokinesis. Moreover, removal of Salv from cardiomyocytes in vivo results in improved cardiac regeneration after adult myocardial infarction, a time when regeneration is usually severely impaired. Here, the authors observed reduced scarring and full restoration of cardiac function. This elegant study suggests that Hippo signalling is a repressor of adult cardiomyocyte renewal and regeneration.

 

Osr2 PAX a punch in palate formation

Precise orchestration of palate formation involves the complex interaction of signalling cascades and transcriptional networks in the developing craniofacial region. Pax9 and Osr2 have previously been implicated in palate formation, but little is known about how these molecular components interact within the greater regulatory network. Now, on p. 4709, Rulang Jiang and colleagues report a crucial role for Pax9 in patterning the anterior-posterior axis as well as outgrowth of the developing palatal shelves. The authors show that Pax9 regulates mesenchyme-epithelium interactions during pattern formation and that the expression of several key genes involved in palate development, such as Shh, Bmp4, Fgf10, Msx1 and Osr2, is reduced in Pax9 mutant mice. Interestingly, expression of Osr2 from the Pax9 locus was able to rescue the posterior, but not anterior, palate formation defect in the absence of Pax9 function. These data place Pax9 upstream of transcription factor Osr2 and signalling molecules Bmp4, Fgf10 and Shh in the molecular network that regulates palate development.

 

Par3 makes contact in migrating mesenchyme

Contact inhibition of locomotion (CIL) is a fundamental regulatory mechanism that ensures correct cell movement and migration. During CIL, cells form transient contacts but the molecular nature of such contacts is unknown. In this issue, Roberto Mayor and colleagues (p. 4763) investigate the role of the cell polarity protein Par3 in microtubule collapse and reorganisation during CIL in migrating neural crest cells. Using antisense morpholinos to Par3 in Xenopus and zebrafish, the authors show that loss of Par3 has a dramatic effect on migration and is essential for CIL both in vitro and in vivo. Par3 knockdowns fail to exhibit microtubule collapse at the cell-cell contact; however, this can be rescued by injection of an antisense morpholino to Trio, implicating the Rac-GEF Trio in migrating neural crest CIL. The authors propose a model in which CIL requires the local destabilisation of microtubules at the cell-cell contacts, which is controlled in a Par3/Trio-dependent manner.

 

Designer flies: accelerated genome editing in Drosophila

The immense power of Drosophila genetics has allowed invaluable insight into developmental biology. Despite these advances, a significant limitation has always been the lack of an efficient method for modifying select genetic loci. Now, on p. 4818, Jean-Paul Vincent and colleagues report high-efficiency homologous recombination in Drosophila with a novel gene-targeting vector. This can be achieved via a two-generation crossing scheme or via direct embryo injection. Importantly, both approaches yield few false-positives due to efficient negative selection, while readily detectable markers aid in the rapid identification of correctly targeted flies. The efficiency can be further increased by co-injecting the sequence-specific endonuclease CRISPR/Cas9. The investigators also report a series of vectors that can be used to insert different genetic elements into the targeted loci, such as mutated or tagged cDNAs and additional reporter genes. Their approach will enable genetic modification in a wide range of contexts, including in postmitotic cells. These tools will be a valuable resource for the Drosophila community.

 

Puffyeye regulates Myc-mediated cell growth

Proper control of cell size is vital to ensure the correct growth and development of any organism. The Myc family of proteins are key regulators of growth, but the mechanisms that control Myc protein levels are complex. Now, on p. 4776, Robert Eisenman and colleagues identify Drosophila Puffyeye (Puf), an orthologue of mammalian USP34, as a novel ubiquitin-specific protease (USP) regulating dMyc-dependant cell growth at the post-translational level. Using genetic interaction experiments, the authors demonstrate that puf opposes the activity of the ubiquitin ligase archipelago (ago) and that Puf acts to stabilise dMyc protein levels. Overexpression of puf in the eye and wing phenocopies dMyc overexpression, while expression of a catalytically inactive form of Puf had no effect, demonstrating the requirement of the Puf USP catalytic domain. Interestingly, the authors demonstrated that Puf can also regulate Ago and Cyclin E protein levels. These data reveal a new mechanism by which dMyc levels can be regulated by USPs in order to fine-tune cell growth.

 

GDF5 determines dendrite growth

Dendrite complexity determines the functional properties of neurons and the overall connectivity of neuronal circuits. The bone morphogenetic protein (BMP) family is known to regulate a myriad of developmental processes, but the extent to which different members of the family are involved in dendrite growth remains unclear. In this issue (p. 4751), Alun Davies and colleagues identify growth differentiation factor 5 (GDF5), a member of the BMP family, as a key regulator of dendrite growth and complexity in the pyramidal neurons of the developing hippocampus. Mice harbouring a mutation in Gdf5 showed dramatically reduced dendrite size and complexity. In vitro, exogenous GDF5 treatment was sufficient to increase elongation of the dendrites, but not the axons, of pyramidal cells derived from the developing mouse hippocampus. The authors further demonstrated that GDF5-mediated dendrite growth acts via the Smad signalling pathway and that GDF5-regulated HES5 expression is both necessary and sufficient for enhanced dendritic growth and complexity.

 

PLUS…

 

Nutritional regulation of stem and progenitor cells in Drosophila

Stem cells and their progenitors are maintained within a microenvironment, termed the niche, but it is known that systemic signals originating outside the niche also affect stem cell and progenitor behavior. Here, Utpal Banerjee and colleagues review recent studies of nutritional effects on stem and progenitor cell maintenance and proliferation in Drosophila. See the Review article on p. 4647

 

Cell-intrinsic drivers of dendrite morphogenesis

The proper formation and morphogenesis of dendrites is fundamental to the establishment of neural circuits in the brain. In this issue, Sidharth Puram and Azad Bonni review cell-intrinsic drivers of dendrite patterning and discuss how the characterization of such regulators advances our understanding of normal brain development and pathogenesis of diverse cognitive disorders. See the Review on p. 4657