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Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth
Alice E. Hughes, … , Sarah E. Flanagan, Andrew T. Hattersley
Alice E. Hughes, … , Sarah E. Flanagan, Andrew T. Hattersley
Published February 21, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI165402.
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Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth

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Abstract

Authors

Alice E. Hughes, Elisa De Franco, Rachel M. Freathy, Sarah E. Flanagan, Andrew T. Hattersley

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Mandibulofacial dysostosis with alopecia results from gain-of-ETAR function via allosteric effects on ligand binding
Yukiko Kurihara, … , Jeanne Amiel, Hiroki Kurihara
Yukiko Kurihara, … , Jeanne Amiel, Hiroki Kurihara
Published January 13, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI151536.
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Mandibulofacial dysostosis with alopecia results from gain-of-ETAR function via allosteric effects on ligand binding

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Abstract

Mutations of G protein coupled receptors (GPCRs) cause various human diseases, but the mechanistic details are limited. Here we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing Mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F. Mouse models carrying either of these missense mutations exhibit a partial maxillary-to-mandibular transformation, which is rescued by deleting the ligand endothelin 3 (ET3/EDN3). Pharmacological experiments confirmed the causative ETAR mutations as gain-of-function, dependent on ET3. To elucidate how an amino acid substitution far from the ligand binding site can increase ligand affinity, we used molecular dynamics (MD) simulations. E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increases flexibility of this portion of the helix, thus favoring G-protein binding and leading to G-protein-mediated enhancement of agonist affinity. The Y129F mutation located under the ligand binding pocket reduces the sodium-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding. These findings provide insight into the pathogenesis of MFDA and into allosteric mechanisms regulating GPCR function, that may provide the basis for drug design targeting GPCRs.

Authors

Yukiko Kurihara, Toru Ekimoto, Christopher T. Gordon, Yasunobu Uchijima, Ryo Sugiyama, Taro Kitazawa, Akiyasu Iwase, Risa Kotani, Rieko Asai, Véronique Pingault, Mitsunori Ikeguchi, Jeanne Amiel, Hiroki Kurihara

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3D imaging analysis on an organoid-based platform guides personalized treatment in pancreatic ductal adenocarcinoma
Ya'an Kang, … , Jason B. Fleming, Michael P. Kim
Ya'an Kang, … , Jason B. Fleming, Michael P. Kim
Published October 25, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI151604.
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3D imaging analysis on an organoid-based platform guides personalized treatment in pancreatic ductal adenocarcinoma

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BACKGROUND. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient derived organoid (PDO) responses to drug treatments and associated tumor-stromal modulation for personalized PDAC therapy. METHODS. We retrospectively quantified apoptotic responses and tumor-stromal cell proportions in patient-derived organoids (PDOs) via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard of care (SOC) regimens. Differences between ODSA results and patient tumor responses were assessed by exact McNemar test. RESULTS. Immunofluorescent signals, organoid growth curves, and Ki-67 levels were measured and authenticated through the OBP for up to 14 days. ODSA drug responses were not different from patient tumor responses as reflected by CA19-9 reductions following neoadjuvant chemotherapy (P = 0.99). PDOs demonstrated unique apoptotic and tumor-stromal modulation profiles (P < 0.0001). α-SMA/CK-19 ratio levels > 1.0 were associated with improved outcomes (P = 0.0179), and longer parental patient survival by Kaplan-Meier analysis (P = 0.0046). CONCLUSION. Heterogenous apoptotic drug responses and tumor-stromal modulation are present in PDOs after SOC chemotherapy. Ratios of α-SMA and CK-19 levels in PDOs are associated with patient survival and the OBP could aid in the selection of personalized therapies to improve the efficacy of systemic therapy in PDAC patients.

Authors

Ya'an Kang, Jenying Deng, Jianhua Ling, Xinqun Li, Yi-Ju Chiang, Eugene J. Koay, Huamin Wang, Jared K. Burks, Paul J. Chiao, Mark W. Hurd, Manoop S. Bhutani, Jeffrey H. Lee, Brian R. Weston, Anirban Maitra, Naruhiko Ikoma, Ching-Wei D. Tzeng, Jeffrey E. Lee, Ronald A. DePinho, Robert A. Wolff, Shubham Pant, Florencia McAllister, Matthew H.G. Katz, Jason B. Fleming, Michael P. Kim

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Relieving Dyrk1a repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes
Kamaleldin E. Elagib, … , Camelia Iancu-Rubin, Adam N. Goldfarb
Kamaleldin E. Elagib, … , Camelia Iancu-Rubin, Adam N. Goldfarb
Published August 4, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI154839.
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Relieving Dyrk1a repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes

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Abstract

Infantile (fetal and neonatal) megakaryocytes have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived megakaryocytes. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with potential to affect MKL1 function and found that Dyrk1a kinase inhibition dramatically enhanced megakaryocyte morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal megakaryocytes. Megakaryocytes derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss of function studies confirmed MKL1 involvement in this morphogenetic pathway. Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results thus delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile megakaryocytes.

Authors

Kamaleldin E. Elagib, Ashton Brock, Cara M. Clementelli, Gohar Mosoyan, Lorrie L. Delehanty, Ranjit K. Sahu, Alexandra Pacheco-Benichou, Corinne Fruit, Thierry Besson, Stephan W. Morris, Koji Eto, Chintan Jobaliya, Deborah L. French, Paul Gadue, Sandeep Singh, Xinrui Shi, Fujun Qin, Robert Cornelison, Hui Li, Camelia Iancu-Rubin, Adam N. Goldfarb

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A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
Danielle E. Whittaker, … , M. Albert Basson, Mehul T. Dattani
Danielle E. Whittaker, … , M. Albert Basson, Mehul T. Dattani
Published November 2, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI141587.
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A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

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The PRDM13 (PR Domain containing 13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

Authors

Danielle E. Whittaker, Roberto Oleari, Louise C. Gregory, Polona Le Quesne Stabej, Hywel J. Williams, John G. Torpiano, Nancy Formosa, Mario J. Cachia, Daniel Field, Antonella Lettieri, Louise A. Ocaka, Alyssa J.J. Paganoni, Sakina H. Rajabali, Kimberley L.H. Riegman, Lisa B. De Martini, Taro Chaya, Iain C. Robinson, Takahisa Furukawa, Anna Cariboni, M. Albert Basson, Mehul T. Dattani

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Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits
Barbara Terzic, … , Marc V. Fuccillo, Zhaolan Zhou
Barbara Terzic, … , Marc V. Fuccillo, Zhaolan Zhou
Published October 15, 2021
Citation Information: J Clin Invest. 2021;131(20):e143655. https://doi.org/10.1172/JCI143655.
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Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

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Abstract

CDKL5 deficiency disorder (CDD) is an early onset, neurodevelopmental syndrome associated with pathogenic variants in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5). CDKL5 has been implicated in neuronal synapse maturation, yet its postdevelopmental necessity and the reversibility of CDD-associated impairments remain unknown. We temporally manipulated endogenous Cdkl5 expression in male mice and found that postdevelopmental loss of CDKL5 disrupts numerous behavioral domains, hippocampal circuit communication, and dendritic spine morphology, demonstrating an indispensable role for CDKL5 in the adult brain. Accordingly, restoration of Cdkl5 after the early stages of brain development using a conditional rescue mouse model ameliorated CDD-related behavioral impairments and aberrant NMDA receptor signaling. These findings highlight the requirement of CDKL5 beyond early development, underscore the potential for disease reversal in CDD, and suggest that a broad therapeutic time window exists for potential treatment of CDD-related deficits.

Authors

Barbara Terzic, M. Felicia Davatolhagh, Yugong Ho, Sheng Tang, Yu-Ting Liu, Zijie Xia, Yue Cui, Marc V. Fuccillo, Zhaolan Zhou

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Foxo1 deletion promotes the growth of new lymphatic valves
Joshua P. Scallan, … , Michael J. Davis, Ying Yang
Joshua P. Scallan, … , Michael J. Davis, Ying Yang
Published July 15, 2021
Citation Information: J Clin Invest. 2021;131(14):e142341. https://doi.org/10.1172/JCI142341.
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Foxo1 deletion promotes the growth of new lymphatic valves

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Patients with congenital lymphedema suffer from tissue swelling in part due to mutations in genes regulating lymphatic valve development. Lymphatic valve leaflets grow and are maintained throughout life in response to oscillatory shear stress (OSS), which regulates gene transcription in lymphatic endothelial cells (LECs). Here, we identified the first transcription factor, Foxo1, that repressed lymphatic valve formation by inhibiting the expression of valve-forming genes. We showed that both embryonic and postnatal ablation of Foxo1 in LECs induced additional valve formation in postnatal and adult mice in multiple tissues. Our quantitative analyses revealed that after deletion, the total number of valves in the mesentery was significantly (P < 0.01) increased in the Foxo1LEC-KO mice compared with Foxo1fl/fl controls. In addition, our quantitative real-time PCR (RT-PCR) data from cultured LECs showed that many valve-forming genes were significantly (P < 0.01) upregulated upon knockdown of FOXO1. To confirm our findings in vivo, rescue experiments showed that Foxc2+/– mice, a model of lymphedema-distichiasis, had 50% fewer lymphatic valves and that the remaining valves exhibited backleak. Both valve number and function were completely restored to control levels upon Foxo1 deletion. These findings established FOXO1 as a clinically relevant target to stimulate de novo lymphatic valve formation and rescue defective valves in congenital lymphedema.

Authors

Joshua P. Scallan, Luz A. Knauer, Huayan Hou, Jorge A. Castorena-Gonzalez, Michael J. Davis, Ying Yang

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Perineuronal net degradation rescues CA2 plasticity in Rett syndrome model mice
Kelly E. Carstens, … , Georgia M. Alexander, Serena M. Dudek
Kelly E. Carstens, … , Georgia M. Alexander, Serena M. Dudek
Published July 6, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI137221.
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Perineuronal net degradation rescues CA2 plasticity in Rett syndrome model mice

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Abstract

Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the human brain of Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we reported that PNNs appear elevated in area CA2 of a human RTT hippocampus and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provided evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8-11) in wildtype mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrated that CA2 PNN development is regulated by Mecp2 and identified a novel window of hippocampal plasticity that is disrupted in a mouse model of RTT.

Authors

Kelly E. Carstens, Daniel J. Lustberg, Emma Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek

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Dysregulation of the NRG1-ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans
Thuy-Linh Le, … , Jeanne Amiel, Nadège Bondurand
Thuy-Linh Le, … , Jeanne Amiel, Nadège Bondurand
Published January 26, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI145837.
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Dysregulation of the NRG1-ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans

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Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system with an incidence of 1/5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in eight individuals variably associating HSCR, CIPO, peripheral neuropathy and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis and intestinal smooth muscle abnormalities. The cell-type-specific ErbB3 and ErbB2 function was further analysed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using RT-qPCR on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing either wild-type or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies including intestinal dysmotility.

Authors

Thuy-Linh Le, Louise Galmiche, Jonathan Levy, Pim Suwannarat, Debby M.E.I. Hellebrekers, Khomgrit Morarach, Franck Boismoreau, Tom E.J. Theunissen, Mathilde Lefebvre, Anna Pelet, Jelena Martinovic, Antoinette Gelot, Fabien Guimiot, Amanda Calleroz, Cyril Gitiaux, Marie Hully, Olivier Goulet, Christophe Chardot, Severine Drunat, Yline Capri, Christine Bole-Feysot, Patrick Nitschke, Sandra Whalen, Linda Mouthon, Holly E. Babcock, Robert Hofstra, Irenaeus F.M. de Coo, Anne-Claude Tabet, Thierry J. Molina, Boris Keren, Alice S. Brooks, Hubert J.M. Smeets, Ulrika Marklund, Christopher T. Gordon, Stanislas Lyonnet, Jeanne Amiel, Nadège Bondurand

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Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy
Anne-Claire Guénantin, … , Nicolas Vignier, Michel Pucéat
Anne-Claire Guénantin, … , Nicolas Vignier, Michel Pucéat
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e136488. https://doi.org/10.1172/JCI136488.
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Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy

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Abstract

LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.

Authors

Anne-Claire Guénantin, Imen Jebeniani, Julia Leschik, Erwan Watrin, Gisèle Bonne, Nicolas Vignier, Michel Pucéat

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