In Development this week (Vol. 143, Issue 21)

Here are the highlights from the current issue of Development:

Signalling cross-talk in the plant root

In plants, root architecture is responsive to environmental changes. The plant hormones cytokinin, auxin and ethylene are known to regulate root growth: cytokinin signalling, acting via type-B ARR effectors, inhibits both proliferation and elongation of root cells, while auxin promotes cell division in the root apical meristem. Various mechanisms exist by which these signalling pathways interact to enable precise spatiotemporal control of root growth. On p. 3982, G. Eric Schaller and colleagues identify another level of cross-talk between these pathways in Arabidopsis. In a screen for regulators of cytokinin-mediated root growth control, they identify mutations in the gene encoding the auxin influx carrier AUX1 that enhance the cytokinin insensitivity of arr mutants. AUX1 seems to be specifically involved in cytokinin-mediated inhibition of root cell elongation but not proliferation. Since AUX1 is required for shootward transport of auxin via the lateral root cap, the authors propose that spatial modulation of this flux controls cell elongation in this region. Moreover, they identify a negative-feedback loop in the system – with ARRs inhibiting AUX1 expression, and AUX1 promoting ARR10expression – that might set up oscillating patterns of hormone flux and gene expression in the root.

Polarisation of the self-organised optic cup

The demonstration that embryonic stem cell (ESC) cultures could self-organise into optic cup-like structures provided a striking and elegant example of the degree to which tissues and organs can self-organise. But outside the embryo context, and in the absence of more global patterning cues, can they adopt appropriate axial identity and polarity? Mototsugu Eiraku and co-workers now investigate dorsoventral (DV) patterning in in vitro formed, mouse ESC-derived optic cups (p. 3895). In vivo, DV polarity is regulated by the Wnt, Shh and BMP pathways, leading to dorsal-specific expression of Tbx5and ventral expression of Vax2. The authors find that these expression domains, and the asymmetric morphogenetic events that form the optic fissure, are largely preserved in ESC-derived optic cups, although less robustly than in vivo. Ventral identity seems to be the default status, with dorsal identity being induced by localised activation of BMP signalling. As in vivo, this is controlled by Wnt signalling, which appears to be induced specifically at the retinal/non-retinal border at one side of the forming optic cup. How this local activation of Wnt is achieved in the in vitro system is unclear, but the data presented highlight the impressive degree to which tissues can self-organise, and demonstrate the utility of this in vitro system for understanding both patterning and morphogenesis.

What do matrix metalloproteinases do in the mammary gland?

During mammary gland development, mammary epithelial tissue undergoes branching morphogenesis to invade the surrounding mammary fat pad. Morphologically, the gland is relatively simple at birth, but undergoes dramatic remodelling during puberty. Based primarily on work in vitro, the matrix metalloproteases MMP14 (MT1-MMP) and MMP15 (MT2-MMP) are thought to play key roles in this branching morphogenesis, both through protease-dependent remodelling of the extracellular matrix and through protease-independent mechanisms. By analysing early (prepubertal) postnatal mammary gland development in mice (p. 3956), Stephen Weiss and colleagues now challenge this model. They find that, in contrast to in vitro data, global deletion of MMP14 or MMP15 has no significant effect on this phase of mammary gland branching, casting doubt on the degree to which proteinase-mediated extracellular matrix remodelling is required for this morphogenetic event. However, the authors also uncover unexpected and differential roles for the two MMPs in adipose development: MMP14 deletion impairs white fat differentiation, while MMP15 mutants show enhanced beige/brown fat formation. The mechanisms underlying this remain unclear, but these data suggest that current models of the roles of these MMPs in mammary gland development may need revising.

Regulating Hh signalling with Rusc

The Hedgehog (Hh) signalling pathway plays multiple fundamental roles during development, yet despite its importance our understanding of the mechanisms regulating pathway activity is still incomplete. Jing Yang and colleagues now identify the Rusc family of RUN and SH3 domain-containing proteins as negative regulators of Hh signalling. In this study (p. 3944) Rusc2 is first identified as an interactor of Sufu – a protein that binds Gli proteins (downstream effectors of the Hh pathway) and suppresses their transcriptional activity. In cell culture, Rusc1 and Rusc2 can inhibit Hh-induced Gli activation in a Sufu-dependent manner. Upon Hh stimulation, Sufu and Gli normally dissociate, allowing Gli translocation to the nucleus. Rusc appears to form a complex with Sufu/Gli in unstimulated cells, and various lines of evidence suggest a model whereby Rusc stabilises the Sufu/Gli complex, and its dissociation upon Hh stimulation is required for Gli activation. Importantly, in vivo experiments in Xenopus embryos are consistent with Rusc1/2 acting as negative regulators of Hh signalling; knockdown of Rusc1 induces phenotypes consistent with Hh pathway overactivation. Thus, this work characterises a new component of the Hh pathway and adds to our understanding of the mechanisms underpinning Hh signal transduction.

A new view of human GnRH neurons

Reproduction in mammals is dependent on specific hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH). During embryonic development, GnRH neurons originate in the nose and migrate to the brain. Here, they release GnRH into the pituitary portal blood circulation for delivery to the pituitary, thus inducing the secretion of fertility-related hormones. Although this system is well studied in mice and other mammals, very little is known about human GnRH neuron development. Here (p. 3969), Paolo Giacobini and colleagues undertake a detailed analysis of the GnRH system in first-trimester human embryos by tracking the origin, migration pattern, final destination and number of GnRH neurons. By applying 3D imaging of solvent-cleared organs (3DISCO) technology to human foetuses for the first time, the authors gain unprecedented insights into the development of the GnRH system, including identifying unexpected migratory routes and brain locations of GnRH neurons. Intriguingly, the authors find a greater number of GnRH neurons than previously thought and reveal that only approximately 20% of these cells colonise the hypothalamus by the end of the first trimester, with the rest being quite widely distributed. While the long-term fate and function of these extra-hypothalamic GnRH neurons remains unclear, their presence raises the possibility of non-fertility-related roles for the GnRH system.

Building bone around blood vessels

It is well known that, in addition to providing nutrients to growing tissues, blood vessels in the developing embryo can play more active roles in directing morphogenesis, patterning and differentiation – primarily through the secretion of signalling molecules. In bone, invasion of blood vessels precedes osteogenesis, and endothelial-derived signalling factors have been shown to regulate ossification. On p. 3933 Elazar Zelzer and co-workers now identify another role for the vasculature in controlling bone morphogenesis. They find that collagen I, the main extracellular matrix component that serves as a template for mineralisation, is deposited by osteoblasts onto endothelial cells within the bone. This is possible because, unlike most blood vessels, vessels within the developing bone are devoid of basement membrane. The collagen-coated vessels then serve as a template for mineral deposition, such that ossification spatially and temporally follows vascular patterning. Notably, disrupting vascularisation of the bone also disrupts bone deposition. This work establishes a previously unrecognised mechanism by which the vasculature regulates bone morphogenesis, and also raises a number of intriguing questions as to the mechanisms underlying the regulation of endothelial basement membrane deposition and the fate of mineralised vessels.

An interview with Paola Arlotta

Paola Arlotta is a neurodevelopmental biologist based at the Harvard Department of Stem Cell and Regenerative Biology in Boston, MA, USA. Her lab studies the birth, differentiation and assembly of neuronal circuits in the cerebral cortex with the aim of developing novel therapies for degenerative and neuropsychiatric diseases. Paola has recently become an editor for Development, and we asked her about her research and career, and her recent efforts to support women in science. See the Spotlight article.

Rebuilding a broken heart: lessons from developmental and regenerative biology

In May 2016, the annual Weinstein Cardiovascular Development and Regeneration Conference was held in Durham, North Carolina, USA. The meeting assembled leading investigators, junior scientists and trainees from around the world to discuss developmental and regenerative biological approaches to understanding the etiology of congenital heart defects and the repair of diseased cardiac tissue. In their Meeting Review, Muge Kuyumcu-Martinez and Michael Bressan present several of the major themes that were discussed throughout the meeting and highlight the depth and range of research currently being performed to uncover the causes of human cardiac diseases and develop potential therapies.

Post-transcriptional modifications in development and stem cells

Cells adapt to their environment by linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. Among these, mechanisms that couple environmental cues to the regulation of protein translation are not well understood. Chemical modifications of RNA allow rapid cellular responses to external stimuli by modulating a wide range of fundamental biochemical properties and processes, including the stability, splicing and translation of messenger RNA. In their  Review, Michaela Frye and Sandra Blanco focus on the occurrence of N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C) and pseudouridine (Ψ) in RNA, and describe how these RNA modifications are implicated in regulating pluripotency, stem cell self-renewal and fate specification.

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