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| Open AccessRetinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools
The heart is formed from several spatiotemporally distinct progenitor pools during development. Here they show that modulation of retinoic acid signaling can instruct human pluripotent stems cells into heart progenitors that are useful for studying human development and disease.
- Dorota Zawada
- , Jessica Kornherr
- & Alexander Goedel
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Article
| Open AccessMuscle cell-type diversification is driven by bHLH transcription factor expansion and extensive effector gene duplications
Different muscle cell types account for specific abilities in animals, yet how their diversification arose remains unclear. Here, the authors show that gene duplications of bHLH transcription factors and effector genes contributed to the diversification of muscle cell types in the sea anemone Nematostella.
- Alison G. Cole
- , Stefan M. Jahnel
- & Ulrich Technau
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| Open AccessSingle-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell development
Cardiac neural crest must differentiate and migrate correctly to achieve proper cardiovascular development. Here, the authors use single cell analyses to show how these cells are altered non-autonomously by loss of Tbx1, the major gene for 22q11.2 deletion syndrome.
- Christopher De Bono
- , Yang Liu
- & Bernice E. Morrow
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Article
| Open AccessTesticular macrophages are recruited during a narrow fetal time window and promote organ-specific developmental functions
How testis resident macrophages develop and influence tissue function is not fully understood. Here the authors use mouse lineage tracing methods to document the haematopoietic source, development and recruitment of early testicular macrophages, support of foetal testis differentiation, and interaction with, and promotion of steroidogenesis in, Leydig cells.
- Xiaowei Gu
- , Anna Heinrich
- & Tony DeFalco
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Article
| Open AccessImmune subset-committed proliferating cells populate the human foetal intestine throughout the second trimester of gestation
The intestine is an important immunological organ in embryonic life, preparing the infant for the microbial colonization following birth. Here authors show that between gestational weeks 14 and 22, the human foetal intestine is first populated by myeloid and innate lymphoid cells, followed by the development of lymphoid cells and a wider range of proliferation-capable immune cell types.
- Nannan Guo
- , Na Li
- & Frits Koning
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Article
| Open AccessZebrafish pigment cells develop directly from persistent highly multipotent progenitors
Neural crest cells are highly multipotent stem cells, but it remains unclear how their fate restriction to specific fates occurs. Here, the authors show in zebrafish that broad multipotency is retained even after migration, suggesting that fate restriction occurs directly, but dynamically.
- Tatiana Subkhankulova
- , Karen Camargo Sosa
- & Robert N. Kelsh
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| Open AccessThe Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency
Signal transduction and gene expression regulation via downstream transcription factors shape the early mammalian embryo. Here the authors show that Wnt/TCF7L1 transcriptional repressive activity is required for primitive endoderm lineage formation.
- Paraskevi Athanasouli
- , Martina Balli
- & Frederic Lluis
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| Open AccessSingle-cell atavism reveals an ancient mechanism of cell type diversification in a sea anemone
Understanding how new cell types arise is essential for understanding the evolution of animal diversity. This study shows that a single gene, NvSox2, acts as a simple switch controlling the development of two alternative types of stinging cells in the sea anemone Nematostella vectensis.
- Leslie S. Babonis
- , Camille Enjolras
- & Mark Q. Martindale
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| Open AccessRepair of airway epithelia requires metabolic rewiring towards fatty acid oxidation
Airway epithelial repair, a key process in the recovery from lung injury, requires a metabolic shift from glycolysis to fatty acid oxidation (FAO). Pharmacological FAO promotion enhances epithelial differentiation, suggesting new therapeutic options.
- Stefania Crotta
- , Matteo Villa
- & Andreas Wack
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| Open AccessGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
β-cell dedifferentiation is a key feature of type 2 diabetes. Here, the authors show evidence of re-differentiation of de-differentiated β-cells and identify ALDH1A3 as a key player in this process, proposing inhibition of ALDH1A3 as a treatment method for β-cell dysfunction in diabetes.
- Jinsook Son
- , Wen Du
- & Domenico Accili
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Article
| Open AccessThe H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs
How the histone variant H2A.Z controls cell fate remains unclear. Here, the authors reveal that the H2A.Z interacting partner HMG20A plays a key role in regulating transcription during early head and heart development.
- Andreas Herchenröther
- , Stefanie Gossen
- & Sandra B. Hake
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Article
| Open AccessEpigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation
Many stem cells exhibit cell division coupled to differentiation, though the changes occurring between consecutive cell divisions have been difficult to study. Here they use synchronized hPSC culture to show that production of transcription factors and epigenetic changes are linked with cell division timing.
- Pedro Madrigal
- , Siwei Deng
- & Siim Pauklin
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Article
| Open AccessDNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells
DNMT3B-dependent DNA methylation provides epigenetic priming at epiblast stage by methylating enhancers of ectodermal genes to ensure proper differentiation toward mesoendoderm tissues.
- Andrea Lauria
- , Guohua Meng
- & Salvatore Oliviero
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Article
| Open AccessJag1-Notch cis-interaction determines cell fate segregation in pancreatic development
Notch signaling is crucial for pancreatic cell fate choice. With mathematical modeling and experiments, Xu et al. provides new insights into how different Notch ligands and Hes1 oscillation guide the spatial-temporal dynamics of cell differentiation.
- Xiaochan Xu
- , Philip Allan Seymour
- & Palle Serup
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| Open AccessA genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Defining cis-regulatory elements is an important goal in understanding how gene expression is regulated. Here the authors show blood cell-specific gene expression is controlled by the action of thousands of differentiation stage-specific sets of cis-elements that respond to cytokine signals terminating at signaling responsive transcription factors.
- B. Edginton-White
- , A. Maytum
- & C. Bonifer
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Article
| Open AccessChanges in PRC1 activity during interphase modulate lineage transition in pluripotent cells
Changes in Polycomb repression during interphase transition modulate the ability of pluripotent cells to enter cell differentiation.
- Helena G. Asenjo
- , María Alcazar-Fabra
- & David Landeira
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| Open AccessThe splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis
Cancer-associated fibroblasts (CAFs) are the main component of the stroma in pancreatic cancer, but their tissue of origin remains to be defined. Here the authors perform lineage tracing and single cell RNA sequencing in mice and suggest the splanchnic mesenchyme as the tissue of origin for CAFs.
- Lu Han
- , Yongxia Wu
- & Gustavo Leone
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| Open AccessSingle-cell transcriptomic analysis identifies murine heart molecular features at embryonic and neonatal stages
A detailed multi-staged single cell atlas of heart development could improve our understanding of cell type diversification during cardiac development. Here, the authors generated a large dataset with cells from embryonic and neonatal hearts to identify the stage and chamber specific features in heart development.
- Wei Feng
- , Abha Bais
- & Guang Li
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Article
| Open AccessLoss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice
SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.
- Damien Dufour
- , Typhanie Dumontet
- & Antoine Martinez
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| Open AccessSt18 specifies globus pallidus projection neuron identity in MGE lineage
The medial ganglionic eminence produces both interneurons and projection neurons, though how this fate choice is made is not well established. Here they show that St18 regulates migration and morphology of MGE neurons, inducing projection neuron fates.
- Luke F. Nunnelly
- , Melissa Campbell
- & Edmund Au
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| Open AccessActivation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration
The epicardium supports heart regeneration, though precisely how is unclear. Here the authors define an activated epicardial progenitor population as the source of essential cell types and paracrine factors for successful heart regeneration in zebrafish.
- Yu Xia
- , Sierra Duca
- & Jingli Cao
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| Open AccessAn atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics
Late prenatal development of the human neocortex encompasses a critical period of gliogenesis and cortical expansion. Here, authors use human transcriptomics to capture transience and diversity of cells in middle and late prenatal development, including glial progenitor signatures.
- Susana I. Ramos
- , Zarmeen M. Mussa
- & Nadejda M. Tsankova
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Article
| Open AccessTBX2 specifies and maintains inner hair and supporting cell fate in the Organ of Corti
Inner hair cells are essential for hearing but the molecular drivers of their differentiation have remained enigmatic. Here, the authors show that the transcription factor TBX2 has a key function in inducing and maintaining inner hair cell fate.
- Marina Kaiser
- , Timo H. Lüdtke
- & Mark-Oliver Trowe
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| Open AccessThe fate of early perichondrial cells in developing bones
In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. Here they show that perichondrial cells are destined to become adipocyte-biased stromal cells, indicating that marrow stromal compartments are defined by their cells of origin.
- Yuki Matsushita
- , Angel Ka Yan Chu
- & Noriaki Ono
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Article
| Open AccessPostnatal expansion of mesenteric lymph node stromal cells towards reticular and CD34+ stromal cell subsets
Lymph nodes in various locations of the body differ in their cell composition and gene expression signatures. Here authors show that the rapid postnatal expansion of lymph nodes is governed by CD34 + stromal cells and fibroblastic reticular stromal cell progenitors, distinguished by intrinsic, microbiome-independent core epigenetic blueprints.
- Joern Pezoldt
- , Carolin Wiechers
- & Jochen Huehn
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Article
| Open AccessPhase separation modulates the assembly and dynamics of a polarity-related scaffold-signaling hub
The polarization of distinct scaffold-signaling hubs at opposite cell poles constitutes the basis of asymmetric cell division. Here, the authors show that phase separation serves as a general mechanism to regulate the assembly and dynamics of a new-pole scaffold-signaling hub.
- Wei Tan
- , Sihua Cheng
- & Wei Zhao
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Article
| Open AccessAlveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling
Here the authors show that FGF signaling initiates alveolus development in mouse lung by inducing AT2 fate and a secondary signal for AT1 fate, and continuously maintains AT2 cells throughout life. FGF inhibition triggers immediate AT2 apoptosis and compensatory regeneration.
- Douglas G. Brownfield
- , Alex Diaz de Arce
- & Mark A. Krasnow
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Article
| Open AccessTransplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism
Hypothyroidism is a common condition that cannot always be satisfactorily treated through continued hormone replacement. Here the authors report the generation of transplantable thyroid organoids derived from human embryonic stem cells that can restore plasma thyroid hormone in athyreotic mice.
- Mírian Romitti
- , Adrien Tourneur
- & Sabine Costagliola
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Article
| Open AccessCHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids
Mutations in the chromatin remodeler CHD7 cause CHARGE syndrome, affecting development of several organs including the inner ear. Here, the authors recapitulated pathogenesis of this disease with human inner ear organoids and found that CHD7 is indispensable for proper otic lineage specification and hair cell differentiation.
- Jing Nie
- , Yoshitomo Ueda
- & Eri Hashino
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| Open AccessHuman multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid
Stem cell models of organogenesis are a valuable tool for the study of human development, but often lack the context of tissue-tissue interaction. Here they generate human multi-lineage organoids comprising pro-epicardium, septum transversum, and liver bud, which they co-culture with heart organoids to generate a physiologically relevant model of organogenesis.
- Mariana A. Branco
- , Tiago P. Dias
- & Maria Margarida Diogo
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Article
| Open AccessSingle-cell profiling reveals a memory B cell-like subtype of follicular lymphoma with increased transformation risk
Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.
- Xuehai Wang
- , Michael Nissen
- & Andrew P. Weng
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| Open AccessOn-microscope staging of live cells reveals changes in the dynamics of transcriptional bursting during differentiation
Here the authors observe transcription dynamics in real-time throughout erythropoiesis by combining PP7 tagging of α-globin RNA transcripts and “on-microscope” cell staging. They show how the pattern of transcriptional bursting changes during differentiation, with variability in individual cells significantly reduced at the peak period of gene expression.
- D. M. Jeziorska
- , E. A. J. Tunnacliffe
- & D. R. Higgs
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| Open AccessUniTVelo: temporally unified RNA velocity reinforces single-cell trajectory inference
RNA velocity can detect the differentiation directionality by modelling sparse unspliced RNAs, but suffers from high estimation errors. Here, the authors develop a computational method called UniTVelo to reinforce the velocity estimation by introducing a unified time and a top-down model design.
- Mingze Gao
- , Chen Qiao
- & Yuanhua Huang
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Article
| Open AccessA hierarchical transcription factor cascade regulates enteroendocrine cell diversity and plasticity in Drosophila
Here the authors elucidate a simple transcription factor code that underlies the complex genetic specification of enteroendocrine cell (EE) subtypes, and reveal significant cellular plasticity amongst EE subtypes.
- Xingting Guo
- , Yongchao Zhang
- & Rongwen Xi
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Article
| Open AccessBrain milieu induces early microglial maturation through the BAX-Notch axis
The mechanisms by which the brain milieu confers microglial development are not clear. Here, the authors show that the BAX-CaMKII-CREB-Notch signaling axis triggered by the neuronal milieu plays a role in early microglia maturation.
- Fangying Zhao
- , Jiangyong He
- & Li Li
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Article
| Open AccessMaintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism
To remain functional throughout life, neuronal cells must maintain the ability to synthesize and release specific neurotransmitters. Here, the authors show that this ability critically depends on the activity of Hox proteins.
- Weidong Feng
- , Honorine Destain
- & Paschalis Kratsios
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| Open AccessEnhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids
Proximal nephron in pluripotent stem cell derived kidney organoids are immature with limited support for functional solute channels. Vanslambrouck et al report improved metanephric specification, generating enhanced kidney organoids with superior proximal tubules, spatially arranged nephrons, and applications for disease research, and drug screening.
- Jessica M. Vanslambrouck
- , Sean B. Wilson
- & Melissa H. Little
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Article
| Open AccessAllosteric regulation of glycogen breakdown by the second messenger cyclic di-GMP
c-di-GMP has emerged as the signal controlling development in antibiotic producing Streptomyces. Here the authors describe another developmental role of c-di-GMP, in energy metabolism, by activating the glycogen-debranchingenzyme, GlgX. Structures revealing the activation mechanism are described.
- Maria A. Schumacher
- , Mirka E. Wörmann
- & Natalia Tschowri
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Article
| Open AccessdevCellPy is a machine learning-enabled pipeline for automated annotation of complex multilayered single-cell transcriptomic data
A major informatic challenge in single cell RNA-sequencing analysis is the precise annotation of datasets where cells exhibit complex multilayered identities or transitory states. Here the authors present devCellPy, a Python-based package that enables the automated prediction of cell types across complex cellular hierarchies, species, and experimental systems with high accuracy, particularly for developmental scRNA-seq datasets.
- Francisco X. Galdos
- , Sidra Xu
- & Sean M. Wu
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Article
| Open AccessThe TFEB-TGIF1 axis regulates EMT in mouse epicardial cells
Epithelial-mesenchymal transition (EMT) is a complex process involved in organogenesis. Here, the authors show that the transcription factor EB (TFEB) regulates EMT in epicardium during heart development by tuning sensitivity to TGFβ signaling.
- Elena Astanina
- , Gabriella Doronzo
- & Federico Bussolino
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Article
| Open AccessMultiscale light-sheet organoid imaging framework
Live imaging of organoid growth remains a challenge: it requires long-term imaging of several samples simultaneously and dedicated analysis pipelines. Here the authors report an experimental and image processing framework to turn long-term light-sheet imaging of intestinal organoids into digital organoids.
- Gustavo de Medeiros
- , Raphael Ortiz
- & Prisca Liberali
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Article
| Open AccessPCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression
Variant Polycomb complexes can have tissue-specific roles during development. Here they show that PCGF6 controls lineage-specification in human PSCs by promoting neuroectoderm differentiation and repressing mesendoderm differentiation via distinct downstream targets.
- Xianchun Lan
- , Song Ding
- & Wei Jiang
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Article
| Open AccessCDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors
Epidermal progenitors are poised for differentiation, which allows for continual balance of self-renewal and differentiation. Here they show that the Super Elongation Complex regulates this process through direct regulation of a set of rapid response genes that involves a CDK9 activity switch.
- Sarah M. Lloyd
- , Daniel B. Leon
- & Xiaomin Bao
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Article
| Open AccessExtensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages
The authors show that the transcription factors NANOG and GATA6 co-bind the same enhancers in common progenitors before divergent epiblast and primitive endoderm lineages emerge. This may help maintain plasticity at early stages and facilitate bifurcation into distinct lineages
- Joyce J. Thompson
- , Daniel J. Lee
- & Pedro P. Rocha
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Article
| Open AccessEtv2 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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Article
| Open AccessStomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth
Stomatin is a component of lipid rafts. Here, Wu et al. show that stomatin modulates the differentiation and functions of adipocytes by regulating adipogenesis signaling and fatty acid influx such that with excessive calorie intake, increased stomatin induces adiposity.
- Shao-Chin Wu
- , Yuan-Ming Lo
- & Chi-Hung Lin
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Article
| Open AccessSomatic cell fate maintenance in mouse fetal testes via autocrine/paracrine action of AMH and activin B
Fate determination and maintenance of foetal testes in most animals occurs cell autonomously. Here the authors show in mouse XY embryos that Sertoli cell derived AMH and activin B together maintain Sertoli cell identity, and lack of both AMH and activin B leads to transdifferentiation into female granulosa cells.
- Karina F. Rodriguez
- , Paula R. Brown
- & Humphrey Hung-Chang Yao
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Article
| Open AccessInterchromosomal interaction of homologous Stat92E alleles regulates transcriptional switch during stem-cell differentiation
Asymmetric inheritance of organelles, proteins and RNAs occurs during stem cell division. Here the authors show the strength of pairing of homologous Stat92E loci, a stem cell-specific gene, changes immediately after the asymmetric division due to asymmetric inheritance of new histones to one of the daughter cells and is important for turning off gene expression in this cell as it differentiates.
- Matthew Antel
- , Romir Raj
- & Mayu Inaba
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Article
| Open AccessA Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells
Fu et al. identify the highly conserved, transmembrane micropeptide, NEMEP, as a direct target of Nodal signaling, essential for mesendoderm differentiation. NEMEP interacts with the glucose transporters GLUT1/GLUT3 and promotes glucose uptake.
- Haipeng Fu
- , Tingyu Wang
- & Qiaoran Xi