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Regulation of long-range BMP gradients and embryonic polarity by propagation of local calcium-firing activity
Identical twins from a single embryo are formed in multiple species, albeit rarely. It is not clear how such twinning is suppressed during early development. Here they show that calcium signalling activity is propagated through the extraembryonic tissue to prevent ectopic primitive streak formation during gastrulation.
- Hyung Chul Lee
- , Nidia M. M. Oliveira
- & Claudio D. Stern
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| Open Access
Diffusible fraction of niche BMP ligand safeguards stem-cell differentiation
The activity of Drosophila male germline stem cells is tightly regulated by a cluster of somatic niche cells. Here they find that Dpp induces opposed cellular responses in stem cells versus in differentiating descendants, thereby ensuring spatial control of the niche with a single factor.
- Sharif M. Ridwan
- , Autumn Twillie
- & Mayu Inaba
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| Open Access
Mcam inhibits macrophage-mediated development of mammary gland through non-canonical Wnt signaling
Mammary epithelial cells act to continuously renew the mammary tissue and must balance differentiation and self-renewal. Here they show that Mcam, a non-canonical Wnt pathway member, regulates communication between macrophages and mammary epithelial cells, thereby maintaining self-renewal and subsequently promoting mammary ductal morphogenesis.
- Xing Yang
- , Haibo Xu
- & Baowei Jiao
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| Open Access
Determining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB
Dorsal organizer initiates the dorsal-ventral axis formation in vertebrates. Here, the authors demonstrate that Tlr4/NFκB-mediated negative feedback regulation of Wnt/β-catenin signaling determines the precise size of the zebrafish dorsal organizer.
- Juqi Zou
- , Satoshi Anai
- & Tohru Ishitani
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The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6
Wnt receptor levels drive signaling. Here the authors find that precise signaling in the Wnt morphogen gradient relies on Usp46, a deubiquitylase that enhances target cells sensitivity by increasing cell surface levels of the Wnt receptor Arrow/LRP6.
- Zachary T. Spencer
- , Victoria H. Ng
- & Yashi Ahmed
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The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling
Wnt receptors are controlled by their ubiquitin-mediated proteolysis. The authors show that the USP46 deubiquitylase complex potentiates Wnt signaling in human cells, Xenopus, and zebrafish by inhibiting cell surface LRP6 degradation.
- Victoria H. Ng
- , Zachary Spencer
- & Ethan Lee
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| Open Access
Time space and single-cell resolved tissue lineage trajectories and laterality of body plan at gastrulation
Gastrulation entails a series of events that are highly coordinated in space and time. Here they construct a spatiotemporal molecular atlas of lineage trajectories in the gastrulating mouse embryo by mapping single cells to spatial coordinates in the germ layers with reference to positional data in the transcriptome.
- Ran Wang
- , Xianfa Yang
- & Naihe Jing
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| Open Access
Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1
Understanding the cellular target of hit compounds from phenotypic screens presents a major challenge yet is essential in the development of chemical probes. Here, the authors reveal the target of Hedgehog Pathway Inhibitor-1, by converting it to a bifunctional degrader, to be BET bromodomains.
- Meropi Bagka
- , Hyeonyi Choi
- & Sascha Hoogendoorn
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| Open Access
Intercellular exchange of Wnt ligands reduces cell population heterogeneity during embryogenesis
Neuromesodermal progenitor (NMP) cells produce and receive Wnt ligands. Here, the authors show that mutual intercellular exchange of Wnt ligands reduces heterogeneity between NMP cells and makes NMP populations robust to environmental stress.
- Yudai Hatakeyama
- , Nen Saito
- & Shinji Takada
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| Open Access
Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing
Fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Here, the authors highlight epithelial integrity as a key determinant of TGF-β activity and a mechanism guiding morphogen sensing and spatial cell fate change.
- Thomas Legier
- , Diane Rattier
- & Rosanna Dono
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Article
| Open Access
Wnt4 and ephrinB2 instruct apical constriction via Dishevelled and non-canonical signaling
Apical constriction is known to be critical for neural tube closure, but the signals that induce this process have not been fully characterized. Here Yoon et al. identify a signaling complex that instructs actomyosin contractions during apical constriction and show that it is required for neural tube closure.
- Jaeho Yoon
- , Jian Sun
- & Ira O. Daar
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Article
| Open Access
Single-molecule tracking of Nodal and Lefty in live zebrafish embryos supports hindered diffusion model
Multiple models have been proposed for how diffusion is regulated to shape morphogen gradients. Here they use single molecule tracking of an activator-inhibitor signaling pair in a developing tissue to show how effective diffusivity is modulated in the extracellular space.
- Timo Kuhn
- , Amit N. Landge
- & J. Christof M. Gebhardt
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Predictive model for cytoneme guidance in Hedgehog signaling based on Ihog- Glypicans interaction
Cytonemes are specialized filopodia-like structures known to be involved in signal transduction. Here they propose a new predictive model for cytoneme guidance in Hedgehog signaling, which is based on Ihog, Dally, and Dlp protein levels.
- Adrián Aguirre-Tamaral
- , Manuel Cambón
- & Isabel Guerrero
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A single WNT enhancer drives specification and regeneration of the Drosophila wing
The wing is a remarkable evolutionary novelty in insects. Here the authors demonstrate that the specification and regenerative capacity of the wing relies on a single wing-specific enhancer of the wingless gene in Drosophila.
- Elena Gracia-Latorre
- , Lidia Pérez
- & Marco Milán
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Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud
The embryonic limb bud is known to be patterned by a Shh morphogen gradient, though how Shh expression is activated remains less clear. Here the authors show that Etv2 acts as a pioneer transcription factor to mediate accessibility of the ZRS enhancer and initiate Shh expression.
- Naoko Koyano-Nakagawa
- , Wuming Gong
- & Daniel J. Garry
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Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
Th17 cells are critical players in the immunopathology of a range of autoimmune diseases. Here the authors implicate Hedgehog signaling in Th17 polarization and in the immunopathology of intestinal inflammation in murine models and suggest therapeutic targeting of Hedgehog signaling in the context of inflammatory bowel disease.
- Joachim Hanna
- , Flavio Beke
- & Maike de la Roche
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Article
| Open Access
GPI-anchored FGF directs cytoneme-mediated bidirectional contacts to regulate its tissue-specific dispersion
Cytonemes are signaling filopodia that mediate target-specific long-distance communications of signals like FGFs. Du et al. show that a Drosophila FGF is anchored to the FGF-producing cell surface, inhibiting free FGF secretion and activating contact-dependent bidirectional FGF-FGFR interactions, controlling target-specific cytoneme contacts and contact-dependent FGF release.
- Lijuan Du
- , Alex Sohr
- & Sougata Roy
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Article
| Open Access
The planarian wound epidermis gene equinox is required for blastema formation in regeneration
Many regenerative animals form an outgrowth at wound sites called a blastema. Here the authors identify equinox, which is expressed in the planarian wound epidermis and essential to initiate positional information regeneration and blastema formation.
- M. Lucila Scimone
- , Jennifer K. Cloutier
- & Peter W. Reddien
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| Open Access
CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids
Although lipids are known to affect Hedgehog (Hh) signalling, the underlying mechanisms remain unclear. Here, the authors show that Canopy4 regulates membrane sterol lipid levels, with knockout mouse embryos exhibiting digit number changes and other Hh signalling-related developmental defects.
- Megan Lo
- , Amnon Sharir
- & Ophir D. Klein
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Cytonemes coordinate asymmetric signaling and organization in the Drosophila muscle progenitor niche
Asymmetric signaling and organization in the stem cell niche determine cell fates. Here the authors show that polarized contact-dependent signaling through specialized cytonemes forms the basis of niche-specific asymmetric signaling and stem cell organization.
- Akshay Patel
- , Yicong Wu
- & Sougata Roy
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| Open Access
GLI transcriptional repression is inert prior to Hedgehog pathway activation
GLI repression has been presumed to be the default transcriptional state and important for pre-patterning tissues. Challenging current models, the authors show that GLI3 repression is inert in the limb bud before the onset of Hedgehog signaling.
- Rachel K. Lex
- , Weiqiang Zhou
- & Steven A. Vokes
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| Open Access
Nodal is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids
Studying morphogen gradient formation and reception in mammalian development is challenging. Here, the authors show with human gastruloids that Nodal activity in live cells spreads via a relay mechanism with timing that is locally controlled by Lefty, which dictates mesoderm differentiation timing.
- Lizhong Liu
- , Anastasiia Nemashkalo
- & Aryeh Warmflash
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| Open Access
Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling
Hedgehog-Interacting Protein (HHIP) is the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling. Here, the authors report structures of the HHIP N- and C-terminal domains, both in complexes with glycosaminoglycans, providing insights into the molecular basis for SHH sequestration and inhibition.
- Samuel C. Griffiths
- , Rebekka A. Schwab
- & Christian Siebold
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Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release
Dispatched (Disp) RND transporter, activated by Furin-mediated proteolytic cleavage, mediates the release of the lipid-modified Hedgehog (Hh) ligands. Here, the authors report structures of human Disp1 (hDisp1) before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh), with insights into the mechanisms of hDisp1 activation and function.
- Wanqiu Li
- , Linlin Wang
- & Xin Gong
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| Open Access
Self-organization of human dorsal-ventral forebrain structures by light induced SHH
Organizing centers act to pattern surrounding tissues during embryogenesis through the secretion of morphogens. Here the authors model human organizers using light stimulus to geometrically confine SHH expression in differentiating hESCs, generating spatially resolved proximal distal patterns.
- Riccardo De Santis
- , Fred Etoc
- & Ali H. Brivanlou
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Article
| Open Access
Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc
Morphogens disperse to pattern tissues and control their growth during development, allowing for the specification of multiple fates across space. Here the authors block dispersal of a morphogen Dpp (BMP2/4) and show that the requirement for Dpp dispersal is much lower than previously thought.
- Shinya Matsuda
- , Jonas V. Schaefer
- & Markus Affolter
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| Open Access
The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling
Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that is involved in cancer cell death, although its regulation is poorly understood. Here, the authors show that Wnt ligand increases CRBN-dependent protein degradation and demonstrate CRBN’s importance in physiological Wnt signaling.
- Chen Shen
- , Anmada Nayak
- & David J. Robbins
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| Open Access
A TALE/HOX code unlocks WNT signalling response towards paraxial mesoderm
Cells in the developing embryo interpret WNT signalling with context-dependence, but the mechanism decoding these cues is unclear. Here, the authors show that combinatorial TALE/HOX activity destabilizes nucleosomes at WNT-responsive regions to activate paraxial mesodermal genes.
- Luca Mariani
- , Xiaogang Guo
- & Elisabetta Ferretti
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| Open Access
SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts
Hedgehog signaling is essential for bone formation. Here, the authors show that the transmembrane protein SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts, suggesting it may be a potential therapeutic target to enhance bone formation.
- Jun Sun
- , Dong Yeon Shin
- & Matthew B. Greenblatt
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Cnidarian-bilaterian comparison reveals the ancestral regulatory logic of the β-catenin dependent axial patterning
The authors show in Nematostella that the more orally expressed β-catenin targets repress the more aborally expressed β-catenin targets, thus patterning the oral-aboral axis. This likely represents the common mechanism of β-catenin-dependent axial patterning shared by Cnidaria and Bilateria.
- Tatiana Lebedeva
- , Andrew J. Aman
- & Grigory Genikhovich
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| Open Access
Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling
Cytonemes are cellular projections known to transfer Wnt ligands between cells, but their regulation remains unclear. Here, the authors show that activation of the planar cell polarity protein Vangl2 generates long and branched cytonemes increasing paracrine Wnt/β-catenin signaling.
- Lucy Brunt
- , Gediminas Greicius
- & Steffen Scholpp
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Article
| Open Access
Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing
Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGFβ signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output.
- Simona Valletta
- , Alexander Thomas
- & Claus Nerlov
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| Open Access
Uncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform
In vitro models of the human mammary gland have struggled to mimic the 3D morphogenic processes that occur in vivo. Here the authors develop a 3D microfluidic platform of a vascularized human mammary duct that simulates diverse morphogenic transitions and paracrine crosstalk.
- Matthew L. Kutys
- , William J. Polacheck
- & Christopher S. Chen
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| Open Access
Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors
In fibrotic biliary disease, portal fibroblasts promote both biliary scarring and bile duct regeneration. Here, the authors report that the non-canonical Wnt-PCP signalling promotes bile duct scarring in mice, and inhibition of Wnt-ligands reduces the scarring without impairing regeneration.
- D. H. Wilson
- , E. J. Jarman
- & L. Boulter
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| Open Access
Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo
Gradients of morphogens such as Wnt provide instructive cues for cell identities during development. Here, the authors report that in the developing zebrafish embryo, cell competition and elimination of unfit cells are required for proper Wnt gradient formation.
- Yuki Akieda
- , Shohei Ogamino
- & Tohru Ishitani
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Article
| Open Access
USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin
Axin is a scaffolding protein known for its role in Wnt signalling that can be marked with a variety of post-translational modifications. Here, Cong et al. demonstrate that USP7 de-ubiquinates Axin and that canonical Wnt signaling output can be increased with USP7 inhibitors.
- Lei Ji
- , Bo Lu
- & Feng Cong
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| Open Access
Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium
KRASG12V and BRAFV600E are oncogenic mutations that activate ERK signalling. Here, the authors use single cell analysis in intestinal organoids and show that BRAFV600E activates ERK in all intestinal cell types, while KRASG12V induces ERK activation in only a subset of cells, depending on cell differentiation state.
- Raphael Brandt
- , Thomas Sell
- & Markus Morkel
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Article
| Open Access
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer
- Tianzuo Zhan
- , Giulia Ambrosi
- & Michael Boutros
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Article
| Open Access
WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis
WNTs can signal over long distances but how this arises in the brain is unclear. Here, the authors show that WNT5A is secreted from the choroid plexus of the developing hindbrain (but not the telencephalon) and transported in the CSF with lipoprotein particles in order to control cerebellar morphogenesis.
- Karol Kaiser
- , Daniel Gyllborg
- & Vítězslav Bryja
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Article
| Open Access
Islr regulates canonical Wnt signaling-mediated skeletal muscle regeneration by stabilizing Dishevelled-2 and preventing autophagy
“Satellite cells are crucial for skeletal muscle regeneration. Here the authors show that immunoglobulin superfamily containing leucine-rich repeat (Islr) promotes skeletal muscle regeneration via a mechanism involving Dishevelled-2 stabilization in satellite cells and protection from autophagy.
- Kuo Zhang
- , Yuying Zhang
- & Qingyong Meng
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Article
| Open Access
SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion
Sustained Wnt secretion requires the endosomal SNX3-retromer complex for endosome-to-trans-Golgi network transport of the internalised Wnt chaperone Wntless. Here the authors show that in both C. elegans and human cells, SNX3-retromer requires an evolutionary conserved membrane remodelling complex for Wntless sorting and Wnt secretion.
- Ian J. McGough
- , Reinoud E. A. de Groot
- & Peter J. Cullen
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Article
| Open Access
Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner
Hippo and Wnt pathways are important for cancer development, and they can cross talk; however, the mechanisms behind this connection are unknown. Here the authors show that DVL (a scaffold protein in the Wnt pathway) regulates the shuttling of YAP (a key component of the Hippo pathway) between cytoplasm and nucleus in specific tumor suppressor contexts.
- Yoonmi Lee
- , Nam Hee Kim
- & Jong In Yook
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Article
| Open Access
Roles of two types of heparan sulfate clusters in Wnt distribution and signaling in Xenopus
Wnt proteins mediate embryonic development but how protein localization and patterning is regulated is unclear. Here, the authors show that distinct structures with different heparan sulfate modifications (‘N-sulfo-rich’ and ‘N-acetyl-rich’) regulate cellular localization and signal transduction of Wnt8 in Xenopus.
- Yusuke Mii
- , Takayoshi Yamamoto
- & Masanori Taira
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Article
| Open Access
Hedgehog mediated degradation of Ihog adhesion proteins modulates cell segregation in Drosophila wing imaginal discs
The range of Hedgehog (Hh) signalling in the Drosophila imaginal disc is limited by Hh/receptor degradation at the anterior/posterior (A/P) compartment boundary. Here, the authors show that degradation is mediated by co-receptor proteins Ihog/Boi, whose cell adhesion functions also contribute to A/P cell segregation.
- Elaine Y. C. Hsia
- , Ya Zhang
- & Xiaoyan Zheng
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Article
| Open Access
High-throughput screens using photo-highlighting discover BMP signaling in mitochondrial lipid oxidation
High-throughput genetic screens in animals could benefit from an easy way to mark positive hits. Here the authors introduce photo-highlighting using a photoconvertible fluorescent protein, and in combination with stimulated Raman scattering (SRS) microscopy, define a role for BMP signaling in lipid metabolism in C. elegans.
- Yong Yu
- , Ayse Sena Mutlu
- & Meng C. Wang
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| Open Access
Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1
Though coronary arteries are crucial for heart function, the mechanisms guiding their formation are largely unknown. Here, Wang et al. identify a unique, endocardially-derived angiogenic precursor cell population for coronary artery formation in mice and show that a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis is key for coronary artery development.
- Yidong Wang
- , Bingruo Wu
- & Bin Zhou
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Article
| Open Access
Lipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells
There are two technical impediments for using purified Wnt proteins in serum-free stem cell cultures: rapid loss of activity and toxicity of detergents to stem cell self-renewal. Here, the authors show that lipid-stabilized Wnt3a can establish long-term culture of human intestinal and liver organoids.
- Nesrin Tüysüz
- , Louis van Bloois
- & Derk ten Berge
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| Open Access
KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling
The ciliary transition zone (TZ) regulates the protein and membrane composition of the primary cilium. Here the authors identify the kinesin-3 motor protein KIF13B as a regulator of TZ membrane composition that controls the ciliary accumulation of Smoothened, which is involved in activation of Sonic hedgehog signalling.
- Kenneth B. Schou
- , Johanne B. Mogensen
- & Lotte B. Pedersen
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Article
| Open Access
TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling
Reduced BMP receptor II signalling underlies pulmonary arterial hypertension (PAH). Here, Hurstet al. show that TNFα subverts BMP signalling by increasing BMP6 expression and signalling via an alternative BMP receptor, ALK2, in pulmonary artery smooth muscle cells to drive abnormal proliferation and PAH.
- Liam A. Hurst
- , Benjamin J. Dunmore
- & Nicholas W. Morrell
Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver