In Development this week (Vol. 142, Issue 22)

Here are the highlights from the current issue of Development:

Nodal: sustaining Shh expression

Underlying the developing vertebrate forebrain is the prechordal mesoderm, which secretes sonic hedgehog (Shh) at a precise developmental time. The tight temporal regulation of this morphogen is crucial for the specification of several ventral cell types in the forebrain. However, little is known about the signals that limit Shh expression temporally. Nodal is expressed in the prechordal mesoderm and had previously been suggested to interact with Shh during ventral forebrain development. Now, using the chick embryo, Marysia Placzek and colleagues (p. 3821) show that Shh expression in the prechordal mesoderm is regulated by proNodal, the precursor of Nodal. Surprisingly, proNodal maintains Shh expression by a non-canonical route: binding to and activating FGFR3. Through this route, proNodal antagonises BMP7 and pSmad1/5/8, which suppresses Shh expression. Together with previous findings, this study suggests that whereas Nodal operates through canonical signalling to induce prechordal mesoderm, it acts via a non-canonical route involving FGFR3 to control the expression of Shh in the prechordal mesoderm.

Hh puts the pressure on boundaries

The Drosophila wing originates as an imaginal disc, which is divided into anterior and posterior domains separated by a straight antero-posterior (AP) boundary. This barrier is characterised by an actomyosin cable and increased mechanical tension at cell junctions, termed cell bond tension. Engrailed and Invected, expressed in the posterior compartment, maintain the straight morphology of the AP boundary both through the induction of the morphogen Hedgehog (Hh) and via an Hh-independent mechanism. How do such signalling pathways regulate cell bond tension at the AP boundary? In this study (p. 3845), Christian Dahmann and co-workers show that the difference in Hh activity between the two compartments drives the local increase in cell bond tension along the AP boundary and is required to bias cell intercalations to maintain its straight shape. Furthermore, increased mechanical tension is generated autonomously at the boundary and does not depend on the actomyosin cable or the Hh-independent mechanism that contributes to the preservation of the AP boundary shape. By linking the molecular players and mechanical determinants, this study sheds light on the mechanisms governing the physical separation of adjacent cell populations destined to different cell fates.

Deciphering genome imprinting

Following fertilisation, a genome-wide demethylation wave reprogrammes the genome. However, in mammals, certain loci can remain methylated specifically on the maternal or paternal chromosome, i.e. imprinted, in somatic cells. It was previously shown in transgenic mice carrying a fragment of the H19imprinting control region (ICR) that the paternally inherited H19 ICR does not need to be methylated in the germline to be imprinted, pointing at the existence of an unknown epigenetic mark inducing post-fertilisation methylation of that locus. Now, using the same H19 ICR transgenic line, Keiji Tanimoto and co-workers (p. 3833) show that H19 ICR imprinting is achieved through maternally inherited DNMT3A- and DNMT3L-mediated de novo methylation. This process is also at play at the endogenous H19 locus. Further, the authors identify the sequences responsible for the post-fertilisation methylation of the transgenic H19 ICR and show that their removal from the endogenous locus leads to partial H19 ICR demethylation and delayed embryonic growth in the offspring that inherited the mutation. These results provide a mechanistic understanding of the contribution of de novo methylation to genomic imprinting in the absence of germline methylation, though the nature of the putative epigenetic mark that directs this methylation has yet to be discovered.

A genome-wide view on cell differentiation

The acquisition of specific cell fates in the early embryo is driven by changes in gene regulatory networks that induce differential expression of effector genes to ultimately instruct a specific cell fate. The activation of such effector genes has been well characterised in time for individual genes, but to a much lesser extent in space. Here (p. 3892), Julius Barsi, Eric Davidson and colleagues performed a quantitative transcriptomic analysis of effector gene activation on a genome-wide scale in six cell populations isolated from different regions of pregastrular and early gastrula sea urchin embryos. With this approach, the authors identify a set of effector gene transcripts shared by the different cell populations. Surprisingly, this shared set of genes is not as large as previously thought. Indeed, the authors show that spatially distinct populations in the early embryo actually display profound differences in effector gene expression long before morphological differences in cell types can be distinguished. This study sheds light on the mechanistic essence of embryonic differentiation and provides a large-scale transcriptomic dataset, a rich resource for the developmental community.

Distilling principles of tubulogenesis

In the developing Drosophila trachea, the maturation of tracheal terminal cells involves the generation of gas-filled tubular branches. However, the mechanism underlying subcellular lumen formation in these cells remains unknown. By adapting high pressure freezing and freeze substitution techniques toDrosophila larvae and performing transmission electron microscopy, Mark Metzstein and Linda Nikolova (p. 3964) show that, contrary to previous belief, lumen formation is not achieved by the direct fusion of cytoplasmic vesicles. Instead, the authors find that it requires a previously undescribed intermediary membrane-lined multivesicular compartment. In this compartment, vesicles assemble and then fuse into a nascent lumen. By further adapting their ultrastructural imaging technique to preserve the fluorescence of protein reporters and performing correlative light and electron microscopy, the authors show that the resolution of the multivesicular intermediate into a mature lumen requires Rabconnectin-3-mediated acidification of the compartment by the V-ATPase proton pump. The tools developed in this study to analyse tubulogenesis in the trachea and the insights provided on the mechanisms underlying this process are likely to contribute to the understanding of lumen formation in other organs.

Hox6: establishing a dialogue during pancreas development

The development of the pancreas, a secretory organ that expands from the endoderm into the surrounding mesoderm-derived mesenchyme, requires a dialogue between its endodermal and mesodermal components. How do these two compartments communicate? To understand the molecular basis of this cellular cross-talk, Deneen Wellik and colleagues (p. 3859) have analysed pancreas organogenesis in mouse, finding that Hox6 genes, a group of patterning genes expressed in the pancreas mesoderm but not in the endoderm, play a crucial role in this process. Indeed, the genetic loss of all Hox6 paralogues results in mild defects in branching and in exocrine differentiation, and a drastic loss of mature endocrine cells. Mechanistically, the authors show that Hox6 depletion results in decreased expression of mesenchymal Wnt5a, a morphogen crucial for pancreas development. This then leads to the loss of the expression of two Wnt inhibitors, Sfrp3 and Dkk1, in endocrine progenitors. Hence, as repression of Wnt signalling in developing endocrine cells is crucial for their differentiation, this study highlights that regional mesodermal patterning cues are essential for the establishment of the mesenchymal/endodermal crosstalk necessary for pancreatic development.

PLUS:

Developing a new look

As you might have noticed, Development has been looking a little different recently, with a new website and a new masthead for the journal. These changes mark the culmination of a series of projects we’ve been working on over the past year at The Company of Biologists. Read more about these changes in the Editorial on p. 3803

Glia in mammalian development and disease

The past few decades have witnessed a flood of studies that detail novel functions for glia in nervous system development, plasticity and disease. Here, Bradley Zuchero and Ben Barres review the origins of glia and discuss their diverse roles during development, in the adult nervous system and in the context of disease. See the Development at a Glance article on p. 3805

Next generation limb development and evolution: old questions, new perspectives

In recent years, systems biology approaches have aided our understanding of the molecular control of limb organogenesis, by incorporating next generation ‘omics’ approaches, analyses of chromatin architecture, enhancer-promoter interactions and gene network simulations based on quantitative datasets into experimental analyses. Here Aimee Zuniga reviews the insights these studies have given into the gene regulatory networks that govern limb development, the fin-to-limb transition and digit reductions during evolution. See the Review on p. 3810

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