In Development this Week (Vol. 144, Issue 13)

Here are the highlights from the current issue of Development:

Heart tube formation: a gut reaction

Morphogenesis of the endoderm-derived foregut (FG) is tightly linked to that of the mesoderm-derived heart tube (HT), with both structures arising at approximately the same time and place in the developing embryo. However, the physical forces that create the FG and HT are unclear. Here, Larry Taber and colleagues combine experimental approaches in chick embryos with computational modelling to explore this issue (p. 2381). They propose that differential anisotropic growth between the mesoderm and endoderm drives tissue folding and formation of the FG while also bringing the bilateral heart fields (HFs) into close proximity. Indeed, inhibition of cell proliferation (using the mitotic inhibitor Aphidicolin) together with computational simulations confirm that proliferation is required for this initial step. They further propose that actomyosin contraction in the anterior intestinal portal (AIP; the caudal opening of the FG) then generates tension that elongates the FG and the fused HFs. In line with this, inhibition of contraction (using the myosin inhibitor blebbistatin) and modelling analyses reveal that contraction is required for FG and HF elongation. Finally, the authors reveal that the fused HFs thicken and expand – driven by an accumulation of cardiac jelly – to eventually create the HT. Together, these findings highlight a new model that integrates HT and FG morphogenesis.

mTORC-ing some sense into pancreas development

In recent years, much progress has been made in uncovering the signalling pathways and transcriptional networks that can influence pancreas development during embryogenesis. However, comparatively little is known about postnatal development of the pancreas, and whether nutrients can impact pancreas development and function after birth. Now, James Wells, Katie Sinagoga and colleagues demonstrate that the nutrient-sensing mTOR pathway regulates the maturation and function of mouse pancreatic islets postnatally (p. 2402). They first reveal that mTOR is dispensable for embryonic development but is required for normal postnatal islet development, with levels of mTOR signalling being highest in the first few weeks after birth. The researchers further report that deletion of mTOR in the endocrine pancreas causes a decrease in islet mass and compromised islet maturation and morphogenesis; this is accompanied by a decrease in islet function. Finally, the authors show that the two known mTOR-containing complexes – mTORC1 and mTORC2 – mediate distinct functions of mTOR: while mTORC1 predominantly regulates islet maturation and function, mTORC2 influences islet mass and morphogenesis. Overall, these findings highlight a potential role for nutrient-sensing mechanisms during postnatal islet development and maturation, a finding that has important implications for deriving functional β-cells in vitro.

A role for cell repulsion during placental labyrinth formation

The placental labyrinth – a complex structure made up of trophoblasts and endothelial cells – provides the interface for gas and nutrient exchange between the embryo and the mother and hence is essential for embryogenesis. However, the molecular mechanisms that underlie the development of this vital labyrinth, particularly those that influence its vascularization, are poorly understood. Here, on p. 2392, Yoshiaki Kubota, Satoru Yamagishi and co-workers report the unexpected finding that fibronectin leucine-rich transmembrane protein 2 (FLRT2), which is a protein that acts as a chemorepellent in neurons, regulates placental labyrinth development in mice. They report that FLRT2 is expressed in endothelial cells specifically in the placental labyrinth. The researchers further demonstrate that the vasculature is poorly formed and aberrantly organized in FLRT2-deficient placentas, with FLRT2-deficient embryos exhibiting high levels of hypoxia. In vitro assays reveal that, as occurs in neurons, FLRT2 signals through UNC5B and can mediate cell repulsion. Following on from this, the authors show that Unc5b deletion recapitulates the vascular defects observed in Flrt2-deficient placentas. Together these exciting results point towards a role for inter-endothelial repulsion, mediated by FLRT2, during placental morphogenesis.

PLUS…

An interview with Bill Harris

William ‘Bill’ Harris is Head of the Department of Physiology, Development and Neuroscience at the University of Cambridge, UK, and a Fellow of both the Royal Society and Academy of Medical Sciences. His lab works on the development of the vertebrate nervous system, with a particular focus on cell lineage in the retina. In 2017 he was awarded the British Society for Developmental Biology’s Waddington Medal for outstanding research performance and services to the community. We met Bill in his Cambridge lab to talk science, art and ice hockey. Read the Spotlight on p. 2307

MicroRNAs in neural development: from master regulators to fine-tuners

The proper formation and function of neuronal networks is required for cognition and behavior. Indeed, pathophysiological states that disrupt neuronal networks can lead to neurodevelopmental disorders such as autism, schizophrenia or intellectual disability. In recent years, it has been shown that microRNAs (miRNAs), an abundant class of small regulatory RNAs, can regulate neuronal circuit development, maturation and function by controlling, for example, local mRNA translation.  Here, Marek Rajman and Gerhard Schratt provide an overview of the most prominent regulatory miRNAs that control neural development, highlighting how they act as ‘master regulators’ or ‘fine-tuners’ of gene expression, depending on context. See the Review on p. 2310

Human haematopoietic stem cell development: from the embryo to the dish

Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and also for recapitulating the development of HSCs from pluripotent stem cells in vitro. Here, Alexander Medvinsky and colleagues discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. They also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field. See the Review on p. 2323

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