Focus 26 January 2021

From molecules and cells to organisms

Living things are a complex, coordinated network of systems, and understanding their basic organization and function integrates multiple levels of biology. This page broadly highlights our most exciting recent publications covering topics from molecular mechanisms of cellular behaviours to organismal physiology.

Featured articles

Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes

Thermogenic adipocytes maintain body temperature in response to cold, but how this is tuned during cold and re-warming is unclear. Here, the authors show HIF2α inhibits beige adipocyte retention, regulating PKA catalysis to control dynamic adipocyte remodelling.
- Ji Seul Han
- Yong Geun Jeon
- Jae Bum Kim
Article Open Access 7 Jun 2022 Nature Communications
Membrane curvature regulates the spatial distribution of bulky glycoproteins

MUC1 is a heavily glycosylated protein on the cell surface. Here the authors show that MUC1 prefers negative over positive membrane curvature due to its bulky size, enabling MUC1 to avoid endocytosis and surface removal based on curvature preference.
- Chih-Hao Lu
- Kayvon Pedram
- Bianxiao Cui
Article Open Access 2 Jun 2022 Nature Communications
Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP

Aggregation of misfolded proteins underlie dementias. Here, the authors show that stressed cells activate an innate mechanism to resolve aggregates of defective proteins in the endoplasmic reticulum, where a third of cellular proteins are produced.
- Eduardo Pinho Melo
- Tasuku Konno
- Edward Avezov
Article Open Access 6 May 2022 Nature Communications
Mapping the cardiac vascular niche in heart failure

The cardiac vascular niche is of major importance in homeostasis and disease, but knowledge of its complexity in response to injury remains limited. Here we combine lineage tracing with single cell RNA sequencing to show alterations in fibroblasts, endothelial and mural cells in hypertrophic remodeling.
- Fabian Peisker
- Maurice Halder
- Rafael Kramann
Article Open Access 31 May 2022 Nature Communications
Exploring the cellular landscape of circular RNAs using full-length single-cell RNA sequencing

Studies of circular RNAs have often been limited to the tissue or organism level. Here, authors investigate the comprehensive expression landscape of circRNAs in human and mouse at single-cell resolution, revealing highly specific and dynamic changes of circRNAs during multiple biological processes.
- Wanying Wu
- Jinyang Zhang
- Fangqing Zhao
Article Open Access 10 Jun 2022 Nature Communications
Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate

While cellular stress shuts down translation, how protein degradation occurs with stress is incompletely understood. The authors describe a stress-induced phase separated organelle that mediates ubiquitin-independent degradation in the proteasome.
- Daniel C. Carrettiero
- Maria C. Almeida
- Kenneth S. Kosik
Article Open Access 2 Jun 2022 Nature Communications
PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling

Fatty acid unsaturation by stearoyl-CoA desaturase 1 (SCD1) protects against cellular stress through unclear mechanisms. Here the authors show 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) is an SCD1-derived signaling lipid that regulates stress-adaption, protects against cell death and promotes proliferation.
- Maria Thürmer
- André Gollowitzer
- Andreas Koeberle
Article Open Access 27 May 2022 Nature Communications
Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism

PKAN and PD are two distinct diseases with overlapping pathophysiology. Here, authors show that their pathogenic genes PANK2 and PINK1 interact. PANK2 regulates mitophagy via CoA metabolism, while PINK1 supervises PANK2 translation on mitochondria.
- Yunpeng Huang
- Zhihui Wan
- Bing Zhou
Article Open Access 3 May 2022 Nature Communications
Mechanical instability generated by Myosin 19 contributes to mitochondria cristae architecture and OXPHOS

The structure of the mitochondrial inner membrane, or cristae, is important for functional oxidative phosphorylation and energy production. Here, the authors show that loss of myosin 19 impairs cristae structure as well as energy production, connecting motor activity to membrane potential.
- Peng Shi
- Xiaoyu Ren
- Congying Wu
Article Open Access 13 May 2022 Nature Communications
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria

Drp1 is the master regulator of mitochondrial fission, which has important impact on cellular functions. Here, Yang et al identified evolutionarily conserved proteins Clueless and its homolog CLUH as key regulators of Drp1 that function via translation of Drp1 receptors MiD49 and Mff.
- Huan Yang
- Caroline Sibilla
- Ming Guo
Article Open Access 24 Mar 2022 Nature Communications
DELE1 tracks perturbed protein import and processing in human mitochondria

Human mitochondria experience substantial stress and malfunction in neurological diseases. Here, the authors reveal DELE1 as a multimodal sensor of protein import and processing defects, rationalizing mitochondrial stress integration.
- Evelyn Fessler
- Luisa Krumwiede
- Lucas T. Jae
Article Open Access 6 Apr 2022 Nature Communications
A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans

Mitochondria regulate diverse cellular signalling processes in addition to producing energy. Here, the authors show a mitochondrial redox switch that, when activated, helps nematode worms sense conditions of low environmental oxygen.
- John O. Onukwufor
- M. Arsalan Farooqi
- Andrew P. Wojtovich
Article Open Access 3 May 2022 Nature Communications
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
Article Open Access 3 May 2022 Nature Communications
ERK1/2 is an ancestral organising signal in spiral cleavage

How invertebrates with spiral cleavage establish their body plans is unclear. Here the authors show that, like molluscs, a basal annelid uses ERK1/2 to instruct body patterning, suggesting that this is a deep ancestral trait in animal embryogenesis.
- Océane Seudre
- Allan M. Carrillo-Baltodano
- José M. Martín-Durán
Article Open Access 28 Apr 2022 Nature Communications
Periodic formation of epithelial somites from human pluripotent stem cells

Somitogenesis has been well characterized in model organisms, resulting in detailed description of the somite segmentation clock. Here they generate somitogenic organoids from human pluripotent stem cells that recapitulate somitogenesis, periodic segmentation, and proper polarity.
- Marina Sanaki-Matsumiya
- Mitsuhiro Matsuda
- Miki Ebisuya
Article Open Access 28 Apr 2022 Nature Communications
Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids

The culture of gastrointestinal organoids relies on Matrigel that has several drawbacks for clinical application. Here, the authors report the feasibility of gastrointestinal tissue-mimetic matrices as effective alternatives to Matrigel for organoid culture and transplantation.
- Suran Kim
- Sungjin Min
- Seung-Woo Cho
Article Open Access 30 Mar 2022 Nature Communications
RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

Lysosomes move along microtubule tracks, and Arl8b is known to stimulate their anterograde transport. Here, the authors identified RUFY3 as an Arl8b effector that interacts with dynein-dynactin to drive retrograde transport and perinuclear lysosome positioning.
- Gaurav Kumar
- Prateek Chawla
- Amit Tuli
Article Open Access 21 Mar 2022 Nature Communications
RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin

Organellar transport is carefully regulated, and endolysosome localized ARL8 is important for kinesin recruitment and anterograde movement. Here, the authors show that RUFY3 and RUFY4 promote retrograde transport of endolysosomes by mediating interaction of ARL8 with dynein-dynactin.
- Tal Keren-Kaplan
- Amra Sarić
- Juan S. Bonifacino
Article Open Access 21 Mar 2022 Nature Communications
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
Article Open Access 4 Mar 2022 Nature Communications
Comparative metabolomics with Metaboseek reveals functions of a conserved fat metabolism pathway in C. elegans

Untargeted mass spectrometry-based metabolomics can reveal new biochemistry, but data analysis is challenging. Here, the authors develop Metaboseek, an open-source software that facilitates metabolite discovery, and apply it to characterize fatty acid alpha-oxidation in C. elegans.
- Maximilian J. Helf
- Bennett W. Fox
- Frank C. Schroeder
Article Open Access 10 Feb 2022 Nature Communications
Tig1 regulates proximo-distal identity during salamander limb regeneration

The mechanisms by which cells determine their position within the 3D space are poorly understood. Research in salamanders offers fresh insights into this question, uncovering Tig1 as a central determinant of proximo-distal identity in regeneration.
- Catarina R. Oliveira
- Dunja Knapp
- Maximina H. Yun
Article Open Access 3 Mar 2022 Nature Communications
An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion

Huntington’s disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.
- Caroline Gubser Keller
- Youngah Shin
- Rajeev Sivasankaran
Article Open Access 3 Mar 2022 Nature Communications
Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4

While RNA interference is conserved across species, small RNA pathways are very diverse. In this study, Gutbrod et al. find that non-canonical roles of Dicer in genome stability are in fact deeply conserved from yeast to humans.
- M. J. Gutbrod
- B. Roche
- R. A. Martienssen
Article Open Access 22 Feb 2022 Nature Communications
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
Article Open Access 10 Feb 2022 Nature Communications
ASPP2 maintains the integrity of mechanically stressed pseudostratified epithelia during morphogenesis

The early embryo maintains its structure in the face of large mechanical stresses during morphogenesis. Here they show that ASPP2 acts to preserve epithelial integrity in regions of high apical tension during early development.
- Christophe Royer
- Elizabeth Sandham
- Shankar Srinivas
Article Open Access 17 Feb 2022 Nature Communications
Mesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing

Developmental and regenerative bone formation require the removal of chondrocytes and matrix. Here the authors show that these processes involve mesenchymal stromal cell-derived septoclasts, which disappear after the completion of development but re-emerge during fracture healing.
- Kishor K. Sivaraj
- Paul-Georg Majev
- Ralf H. Adams
Article Open Access 28 Jan 2022 Nature Communications
Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development

The molecular basis and gene regulatory networks driving pharyngeal endoderm development remain poorly understood. Here the authors report single cell transcriptomic and chromatin landscapes to delineate regulatory programs driving this process and to define the immunodeficiency-associated developmental defects resulting from Foxn1 dysfunction.
- Margaret E. Magaletta
- Macrina Lobo
- René Maehr
Article Open Access 24 Jan 2022 Nature Communications
Constitutive activation of canonical Wnt signaling disrupts choroid plexus epithelial fate

The cerebrospinal fluid-secreting choroid plexus needs a balanced level of canonical Wnt signaling. Here the authors show that if this signaling is over-activated, the choroid plexus loses its properties and function, and transforms to a neuronal identity.
- Arpan Parichha
- Varun Suresh
- Shubha Tole
Article Open Access 2 Feb 2022 Nature Communications
Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling

The small intestine forms via crosstalk between epithelial and mesenchymal cell compartments. Here, the authors show that a gradient of Wnt signalling along the anterior-posterior axis regulates Sonic Hedgehog which is required for correct formation and regionalization of the small intestine.
- Martti Maimets
- Marianne Terndrup Pedersen
- Kim B. Jensen
Article Open Access 7 Feb 2022 Nature Communications
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
Article Open Access 25 Jan 2022 Nature Communications
Identification of a modular super-enhancer in murine retinal development

Super-enhancers are regions of genomic DNA comprised of multiple putative enhancers that contribute to dynamic gene expression patterns during development. Here the authors identify a modular super-enhancer in murine retinal development and show that distinct modules are responsible for retinal progenitor cell proliferation during early and bipolar neuron genesis during late retinal development.
- Victoria Honnell
- Jackie L. Norrie
- Michael A. Dyer
Article Open Access 11 Jan 2022 Nature Communications
Breaking constraint of mammalian axial formulae

Vertebral column length and shape exhibits remarkable robustness within a species but diversity across species. Here the authors reveal the molecular logic constraining vertebral number in mouse and a novel role for posterior Hox genes in this context.
- Gabriel M. Hauswirth
- Victoria C. Garside
- Edwina McGlinn
Article Open Access 11 Jan 2022 Nature Communications
Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

Mutations in the human WDR81 gene result in severe microcephaly. Carpentieri et al. show that mutation of WDR81, a gene coding for an endosomal regulator, alters intracellular processing of the EGF receptor, leading to reduced proliferation rates of neuronal progenitors and to microcephaly.
- Jacopo A. Carpentieri
- Amandine Di Cicco
- Alexandre D. Baffet
Article Open Access 10 Jan 2022 Nature Communications
2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA

It has been a longstanding goal to promote the propagation of functional mitochondrial DNAs at the expense of pathological molecules in cells where the two species coexist. Here, the authors show that restricting the availability of glucose and glutamine can achieve this outcome.
- Boris Pantic
- Daniel Ives
- Antonella Spinazzola
Article Open Access 6 Dec 2021 Nature Communications
WFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells

The role of cargo receptors in proinsulin export from the ER is unclear. Here, the authors identify the WFS1 protein, which is mutated in Wolfram syndrome and associated with diabetes, as an ER to Golgi cargo receptor required for normal insulin processing and secretion.
- Linlin Wang
- Hongyang Liu
- Zonghong Li
Article Open Access 30 Nov 2021 Nature Communications
Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution

Protein activity regulated by phosphorylation can result in subcellular relocation. Here, the authors present a high throughput spatial phosphoproteomics approach to profile six subcellular compartments, providing insights into EGFR and stress signalling dynamics.
- Ana Martinez-Val
- Dorte B. Bekker-Jensen
- Jesper V. Olsen
Article Open Access 7 Dec 2021 Nature Communications
Spatial control of avidity regulates initiation and progression of selective autophagy

The molecular principles governing the initiation of autophagosome formation are not clearly understood. Here we show that the vacuolar protein Vac8 coordinates this process by promoting an avidity-driven assembly of several autophagy factors.
- David M. Hollenstein
- Mariya Licheva
- Claudine Kraft
Article Open Access 10 Dec 2021 Nature Communications
Cilia locally synthesize proteins to sustain their ultrastructure and functions

Cilia are microtubule-based organelles containing proteins transported from the cell body. Here, the authors show that the multicilia of mouse ependymal cells contain ribosomal components, tubulin mRNA,18 S rRNA and nascent tubulin peptides, suggesting local translation in the ciliary compartment.
- Kai Hao
- Yawen Chen
- Xueliang Zhu
Article Open Access 30 Nov 2021 Nature Communications
Hox genes regulate asexual reproductive behavior and tissue segmentation in adult animals

Hox genes are highly conserved and well-known for their role in segmental patterning during early development. Here, the authors identify an unreported role for Hox genes in the adult tissue patterning and fission behavior required for asexual reproduction in planarian flatworms.
- Christopher P. Arnold
- Analí Migueles Lozano
- Alejandro Sánchez Alvarado
Article Open Access 18 Nov 2021 Nature Communications
Tissue fluidity mediated by adherens junction dynamics promotes planar cell polarity-driven ommatidial rotation

Ommatidial rotation in the Drosophila eye is a regulated process and a Planar Cell Polarity (PCP) cell motility model. Here, the authors show that tissue fluidity via junctional remodeling, as regulated by the PCP effector kinase Nemo, is critical for this cell motility process.
- Nabila Founounou
- Reza Farhadifar
- Marek Mlodzik
Article Open Access 30 Nov 2021 Nature Communications
Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm

Perturbations of the cardiopharyngeal mesoderm can lead to congenital defects in individuals with 22q11.2 deletion syndrome. Here the authors use single cell RNA-sequencing to identify a multilineage primed population within the mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells.
- Hiroko Nomaru
- Yang Liu
- Bernice E. Morrow
Article Open Access 17 Nov 2021 Nature Communications
The autophagy protein ATG9A enables lipid mobilization from lipid droplets

ATG9A is transmembrane autophagic machinery protein that delivers phospholipids to expanding autophagosomes. Mailler et al. show that ATG9A is required to mobilize lipids from lipid droplets for autophagosome expansion as well as mitochondrial fatty acid import and β-oxidation.
- Elodie Mailler
- Carlos M. Guardia
- Juan S. Bonifacino
Article Open Access 19 Nov 2021 Nature Communications
Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways

The role of the transcriptional effector SMAD4 in vertebrate embryo development remains unresolved. Here the authors show that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling, while Nodal signaling is maintained, but insufficient for optimal endoderm specification.
- Luca Guglielmi
- Claire Heliot
- Caroline S. Hill
Article Open Access 4 Nov 2021 Nature Communications
Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation

Heteroplasmic mtDNA mutations cause disease in humans. Here, Chung et al find the PI3K-Akt-mTORC1 pathway constitutively activated in cells with the heteroplasmic m.3243 A > G mutation, and inhibition of the pathway cell autonomously reduces mutant mtDNA load and rescues mitochondrial bioenergetics.
- Chih-Yao Chung
- Kritarth Singh
- Michael R. Duchen
Article Open Access 4 Nov 2021 Nature Communications
Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity

Neutrophils migrate with remarkably stable front-rear polarization. Using optogenetic receptor control to induce reversal of polarization in restrictive microfluidic channels, the authors find that myosin II promotes this stability by suppressing transmission of receptor inputs at the cell rear.
- Amalia Hadjitheodorou
- George R. R. Bell
- Julie A. Theriot
Article Open Access 16 Nov 2021 Nature Communications
Optogenetic control of receptors reveals distinct roles for actin- and Cdc42-dependent negative signals in chemotactic signal processing

Here the authors use optogenetic tools to directly measure spatial signal processing in leukocyte chemotaxis. Their results reveal the importance of multiple negative feedback loops for maintaining spatial information in chemotaxis.
- George R. R. Bell
- Esther Rincón
- Sean R. Collins
Article Open Access 16 Nov 2021 Nature Communications
A metabolome atlas of the aging mouse brain

Metabolites play an important role in physiology, yet the complexity of the metabolome and its interaction with disease and aging is poorly understood. Here the authors present a comprehensive atlas of the mouse brain metabolome and how it changes during aging.
- Jun Ding
- Jian Ji
- Oliver Fiehn
Article Open Access 15 Oct 2021 Nature Communications
Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice

Misregulation of chromatin has been linked to many conditions, including obesity, but the details remain unclear. Here the authors identify the H4 lysine 16 acetyltransferase MOF as a master regulator of glucose metabolism that is required for normal glucose uptake and fat storage.
- Cecilia Pessoa Rodrigues
- Aindrila Chatterjee
- Asifa Akhtar
Article Open Access 27 Oct 2021 Nature Communications
p107 mediated mitochondrial function controls muscle stem cell proliferative fates

The connection between cell cycle, metabolic state and mitochondrial activity is unclear. Here, the authors show that p107 represses mitochondrial transcription and ATP output in response to glycolytic byproducts, causing metabolic control of the cell cycle rate in myogenic progenitors.
- Debasmita Bhattacharya
- Vicky Shah
- Anthony Scimè
Article Open Access 13 Oct 2021 Nature Communications
GAK and PRKCD are positive regulators of PRKN-independent mitophagy

The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remain elusive. Here the authors use an siRNA library to screen lipid-binding proteins, and identify the kinases GAK and PRKCD as positive regulators of PRKN-independent mitophagy.
- Michael J. Munson
- Benan J. Mathai
- Anne Simonsen
Article Open Access 20 Oct 2021 Nature Communications

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