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Condensin-mediated restriction of retrotransposable elements facilitates brain development in Drosophila melanogaster
Mutations in condensin subunits cause microcephaly, but the underlying molecular mechanisms remain elusive. Here, the authors show that unrestricted retrotransposable element activity impairs brain development in condensin insufficient organisms.
- Bert I. Crawford
- , Mary Jo Talley
- & Michelle S. Longworth
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fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
Extraocular muscles remain unaffected in muscular dystrophies. Here, the authors show that the gene fhl2b has a protective role in extraocular muscle and that its protective function can be applied to rescue other muscles in a zebrafish model of muscular dystrophy.
- Nils Dennhag
- , Abraha Kahsay
- & Fatima Pedrosa Domellöf
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TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome
THOC6 is required for TREX tetramer formation. Analysis of pathogenic THOC6 variants differentiate the conserved mRNA export functions of TREX dimers and RNA processing functions of TREX tetramers underlying THOC6 Intellectual Disability Syndrome.
- Elizabeth A. Werren
- , Geneva R. LaForce
- & Ashleigh E. Schaffer
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Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of murine juvenile myogenic progenitors
The establishment of the postnatal skeletal muscle stem cell pool is not well understood. Here the authors show a requirement for Nf1 to coordinate muscle fiber growth and stem cell quiescence induction, and to prevent detrimental metabolic reprogramming with life-long consequences.
- Xiaoyan Wei
- , Angelos Rigopoulos
- & Sigmar Stricker
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Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
A vesicle trafficking Rab11 effector switch is important for ciliogenesis. Here, the authors report a ciliopathy-related disorder caused by variants in WDR44, a Rab11 effector. WDR44 variants show higher affinity for Rab11 and can impair ciliogenesis.
- Andrea Accogli
- , Saurabh Shakya
- & Christopher J. Westlake
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Cytoglobin regulates NO-dependent cilia motility and organ laterality during development
Developmental defects in left-right cardiac determination in humans are associated with ciliary dysfunction and low airway epithelial nitric oxide production. Here, the authors show that cytoglobin is essential for nitric oxide signaling, cilia function, and left-right patterning during zebrafish development.
- Elizabeth R. Rochon
- , Jianmin Xue
- & Paola Corti
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RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis
Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) arises from mutations in Angiotensin II sensing genes, but how they impact the kidney was unclear. This study reveals that delayed angiogenesis at a critical developmental window underlies AR-RTD.
- Naomi Pode-Shakked
- , Megan Slack
- & Raphael Kopan
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SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability
Pubertal timing in mammals depends on the function of GnRH neurons that innervate the median eminence (ME) of the hypothalamus. Here, the authors show that Semaphorin 6A regulates GnRH innervation and puberty onset by tuning vascular permeability at the ME.
- Antonella Lettieri
- , Roberto Oleari
- & Anna Cariboni
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Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice
Myelination is often compromised in ATR-X intellectual disability syndrome patients. Here, the authors show that the causative gene, ATRX, can regulate myelination in mice by modulating systemic thyroxine levels and by supporting oligodendrocyte progenitor differentiation.
- Megan E. Rowland
- , Yan Jiang
- & Nathalie G. Bérubé
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Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
The normal function of amyloid precursor protein (APP) implicated in Alzheimer’s disease is unclear. Here, authors use multi-omics to reveal the fly APP’s role in regulating proteostasis and validate using vertebrate and In-vivo tauopathy models.
- Vanitha Nithianandam
- , Hassan Bukhari
- & Mel B. Feany
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PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
A coding variant of the PAX4 transcription factor (p.Arg192His) is uniquely associated with Type 2 Diabetes in East Asian populations. Here, the authors show that two different coding gene variants of PAX4, p.Arg192His and the newly identified p.Tyr186X, can influence pancreatic beta cell development, identity, and function.
- Hwee Hui Lau
- , Nicole A. J. Krentz
- & Adrian Kee Keong Teo
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A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells
Here the authors study how BRCA2 mutations affect mammary epithelial subpopulations. They report that Brca2mut/WT mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2mut/WT HR- luminal cells.
- Maryam Ghaderi Najafabadi
- , G. Kenneth Gray
- & Mona Shehata
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Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
The SART3 gene encodes an RNA-binding protein critical for spliceosome function. Here, the authors find that bi-allelic variants in SART3 underlie a congenital condition characterised by neuro-developmental defects and 46,XY gonadal dysgenesis.
- Katie L. Ayers
- , Stefanie Eggers
- & Andrew H. Sinclair
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Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction
Cleft lip and palate is a common birth defect thought to involve both genetic and environmental components in its etiology. Here they identify a mechanism involving inflammation and E-cadherin mutations that reduces neural crest migration, leading to craniofacial defects.
- Lucas Alvizi
- , Diogo Nani
- & Roberto Mayor
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Isthmin-1 (Ism1) modulates renal branching morphogenesis and mesenchyme condensation during early kidney development
Loss of Ism1 in mice results in kidney agenesis and dysplasia that are common human diseases. Here they show that Ism1 is expressed in metanephric mesenchyme and acts as a ligand of Integrin α8β1 to regulate mesenchyme condensation during early renal branching morphogenesis.
- Ge Gao
- , Xiaoping Li
- & Zhongjun Zhou
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Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.
- Deivid C. Rodrigues
- , Marat Mufteev
- & James Ellis
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Retinoic 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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Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation
In this work, the authors demonstrate that LLPS of the quaternary USH2 protein complex initiates the formation of stereociliary ankle link condensates, providing insights into the pathogenesis of deafness.
- Huang Wang
- , Haibo Du
- & Qing Lu
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Single-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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BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism
Osteoclast differentiation is critical for bone homeostasis. The authors show the negative feedback regulation of BRD9-mediated chromatin remodeling on osteoclastogenesis via interferon beta signaling and its therapeutic potential for bone diseases.
- Jiahui Du
- , Yili Liu
- & Xinquan Jiang
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Loss 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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Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Dysregulation of the post-translational modification neddylation has been implicated in liver diseases such as fibrosis and hepatocellular carcinoma. Here the authors report that hepatic neddylation deficiency via genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1) causes acute liver failure due to mitochondrial dysfunction and aberrant activation of NF-κB-inducing kinase in mice.
- Cheng Xu
- , Hongyi Zhou
- & Weiqin Chen
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Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
Renal tubular epithelial cells (TECs) can initiate an adaptive or maladaptive response after injuries of different severity. Here, the authors elucidate a chromatin-mediated mechanism underlying the responses of TECs to varying kidney injuries.
- Xinyi Cao
- , Jiuchen Wang
- & Lirong Zhang
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Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
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CHD7 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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Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish
Disruptions to the ER-Golgi network can lead to neurodevelopmental disorders, though our understanding of these Golgipathies remains incomplete. Here Lauri, Tartaglia and colleagues show that ARF3 mutations cause a rare pediatric neurological disorder and perform detailed molecular characterization in fish.
- Giulia Fasano
- , Valentina Muto
- & Marco Tartaglia
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Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
LMNA mutations cause severe heart dysfunction. Here the authors show that Lamin A/C plays a key role in 3D chromatin architecture in naïve pluripotent stem cells, which ensures proper cardiovascular cell fate and function, and shed light on the mechanisms involved in LMNA cardiomyopathies.
- Yinuo Wang
- , Adel Elsherbiny
- & Gergana Dobreva
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The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8+ T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
- Vikash Chandra
- , Hazem Ibrahim
- & Timo Otonkoski
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Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome
The developmental mechanisms responsible for the structural defects observed in hypoplastic left heart syndrome remain controversial. Using rbfox-deficient zebrafish, the authors implicate impaired cardiac function as a primary driver of disease.
- Mengmeng Huang
- , Alexander A. Akerberg
- & Caroline E. Burns
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A SOX17-PDGFB signaling axis regulates aortic root development
Little is known about the developmental causes of aortic root defects. Here the authors show that the inactivation of Sox17 in aortic root endothelium results in aortic root defects affecting aortic valve and coronary ostium.
- Pengfei Lu
- , Ping Wang
- & Bin Zhou
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SpG and SpRY variants expand the CRISPR toolbox for genome editing in zebrafish
The recent development of PAM-less base editors makes it possible to assess the functional impact and pathogenicity of nucleotide mutations in animals. Here the authors show that SpG and SpRY could edit NGN and NNN PAMs in zebrafish using the purified protein with synthetically modified gRNA, respectively.
- Fang Liang
- , Yu Zhang
- & Wei Qin
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Environmental cues from neural crest derivatives act as metastatic triggers in an embryonic neuroblastoma model
Neuroblastoma is characterised by cell types that feature mesenchymal like or sympathetic noradrenergic transcriptional profiles. Here, the authors show that exogenous factors secreted by sympathetic ganglion cells modulate these profiles, activating gene programs promoting the metastatic process.
- Dounia Ben Amar
- , Karine Thoinet
- & Valérie Castellani
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Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.
- Yun Zhang
- , Shuaijun Li
- & Lei Cui
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Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling
The molecular mechanisms through which pulmonary endothelial progenitor cells stimulate lung angiogenesis are not clear. Here, authors show that these cells stimulate the growth of alveolar capillaries and alveoli of newborn mice through FOXF1 and FLI1 nuclear protein-activation of the BMP9/ACVRL1/SMAD1 signaling pathway.
- Guolun Wang
- , Bingqiang Wen
- & Vladimir V. Kalinichenko
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Loss of the Bardet-Biedl protein Bbs1 alters photoreceptor outer segment protein and lipid composition
Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Here they identify a role for Bbs1 in lipid homeostasis of photoreceptor outer segments in zebrafish, which may contribute to vision loss in patients with Bardet-Biedl syndrome.
- Markus Masek
- , Christelle Etard
- & Ruxandra Bachmann-Gagescu
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Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy
Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.
- Tiffany Chern
- , Annita Achilleos
- & Ross A. Poché
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Maternal regulation of biliary disease in neonates via gut microbial metabolites
The pathogenesis of biliary atresia remains poorly understood. Here, the authors report that maternal butyrate treatment alters the gut microbiome and glutamine/hypoxanthine metabolites similar to human subjects, and suppresses biliary atresia in newborn mice.
- Jai Junbae Jee
- , Li Yang
- & Jorge A. Bezerra
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Single-cell analysis identifies a key role for Hhip in murine coronal suture development
Craniofacial development depends on formation and maintenance of sutures between bones of the skull. Here the authors identify enriched expression of the hedgehog inhibitor Hhip, specifically in the mesenchyme of the murine coronal suture, and show sutural dysgenesis in Hhip−/− mutants.
- Greg Holmes
- , Ana S. Gonzalez-Reiche
- & Ethylin Wang Jabs
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A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
It is unknown why infant acute lymphoblastic leukemia (ALL) produced by MLL rearrangements leads to worse outcomes than childhood ALL. Here the authors develop a CRISPR-Cas9-induced human xenograft model of MLL-AF4 infant-ALL that faithfully replicates the disease and reveals that fetal-specific genes are potential infant-ALL drivers.
- Siobhan Rice
- , Thomas Jackson
- & Anindita Roy
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Article
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A tissue-bioengineering strategy for modeling rare human kidney diseases in vivo
The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here the authors present a tissue bioengineering strategy for the study of a rare kidney tumor called angiomyolipoma, in vitro and in vivo, using patient-derived hiPSCs.
- J. O. R. Hernandez
- , X. Wang
- & D. R. Lemos
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Article
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A human multi-lineage hepatic organoid model for liver fibrosis
Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder which is associated with kidney and liver pathology, including liver fibrosis. Here the authors develop and characterize human liver organoids with a ARPKD mutation, and find that they show aspects of the pathology, including fibrosis.
- Yuan Guan
- , Annika Enejder
- & Gary Peltz
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Bardet-Biedl syndrome proteins modulate the release of bioactive extracellular vesicles
Extracellular vesicles (EV) are known to be released from the primary cilium, but the role ciliary proteins play in EV biogenesis remains unexplored. Here, the authors demonstrate increased secretion of small EVs with altered cargo composition from cells with known ciliarelated mutations. Wnt related molecules made up a majority of altered cargo
- Ann-Kathrin Volz
- , Alina Frei
- & Helen L. May-Simera
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Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity
Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.
- Endika Haro
- , Florence Petit
- & Kerby C. Oberg
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The developing mouse coronal suture at single-cell resolution
The development of the coronal suture remains incompletely understood. Here the authors perform scRNA-seq and expression validation to uncover the cellular diversity within the murine embryonic coronal suture, thus revealing possible mechanisms for its loss in craniosynostosis.
- D’Juan T. Farmer
- , Hana Mlcochova
- & Stephen R. F. Twigg
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Article
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SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome
Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
- Federica Banfi
- , Alicia Rubio
- & Alessandro Sessa
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Maternal iron deficiency perturbs embryonic cardiovascular development in mice
From mouse experiments, the authors link iron deficiency in mothers with cardiovascular defects and increased retinoic acid signalling in their offspring, and giving iron early in pregnancy can prevent most defects.
- Jacinta I. Kalisch-Smith
- , Nikita Ved
- & Duncan B. Sparrow
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Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype
Subunits of the Elongator complex have been implicated in several nervous system pathologies. Here, the authors identify ELP2 variants in six patients with neurodevelopmental anomalies and show in mouse models that these variants impact protein stability and the activity of the complex during brain development.
- Marija Kojic
- , Tomasz Gawda
- & Brandon J. Wainwright
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Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice
Mutations that cause tissue mosaicism have been identified in individuals with severe congenital defects. Here, the authors show that mosaic deletion of Vangl2 in the murine neuroepithlium causes spina bifida by preventing apical constriction via reduced myosin II and tubulin organisation.
- Gabriel L. Galea
- , Eirini Maniou
- & Andrew J. Copp
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The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus
Mutations in the MLL4 gene can cause Kabuki syndrome, whose underlying molecular mechanisms are unclear. Here, the authors show that Mll4 epigenetically regulates the transcriptional program leading to the formation of GHRH-neurons in the developing mouse hypothalamus.
- Christian Huisman
- , Young A. Kim
- & Jae W. Lee
A conserved NR5A1-responsive enhancer regulates SRY in testis-determination