Digital Commons Network^™

Loss Of Dihydroceramide Desaturase Drives Neurodegeneration By Disrupting Endoplasmic Reticulum And Lipid Droplet Homeostasis In Glial Cells, Yuqing Zhu, Kevin Cho, Haluk Lacin, Yi Zhu, Jose T Dipaola, Beth A Wilson, Gary Patti, James B Skeath

2020-Current year OA Pubs

Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that

Danicamtiv Reduces Myosin's Working Stroke But Activates The Thin Filament By Accelerating Actomyosin Attachment, Brent Scott, Lina Greenberg, Caterina Squarci, Kenneth S Campbell, Michael J Greenberg

2020-Current year OA Pubs

Heart failure is a leading cause of death worldwide, and even with current treatments, the 5-y transplant-free survival rate is only ~50 to 70%. As such, there is a need to develop new treatments for patients that improve survival and quality of life. Recently, there have been efforts to develop small molecules for heart failure that directly target components of the sarcomere, including cardiac myosin. Danicamtiv is one of these molecules; however, its direct effects on myosin's single molecule mechanics and kinetics are not well understood. Using optical trapping techniques, stopped flow transient kinetics, and in vitro reconstitution assays, we …

Building An Interdisciplinary Workforce In Geroscience: Aligning Perspectives And Educational Goals, Iman M Al-Naggar, Miranda E Orr, Et Al.

2020-Current year OA Pubs

The National Institute on Aging-funded Geroscience Education and Training Network held the "Building an Interdisciplinary Workforce in Geroscience: Aligning Perspectives and Educational Goals" preconference workshop at the 2023 Gerontological Society of America's Annual Meeting. Parties involved in geroscience education and interested stakeholders addressed the development of didactic educational materials, training, and career development opportunities to equip learners with the skills to meet the demands of the emerging field of geroscience, from research to clinic and industry. Recent successes were presented, existing opportunities, gaps, and challenges identified and discussed, and solutions and future directions described.

Unleashing Nk Cells For Cancer Immunotherapy In Lung Cancer: Biologic Challenges And Clinical Advances, Quinlan Mclaughlin, Dorothy K Sojka, Kathleen Kennedy, Sytse J Piersma, Nan Sethakorn

2020-Current year OA Pubs

Natural killer (NK) cells are a crucial part of the innate immune system and serve as an important effector for killing tumor cells through direct cytolytic activity or immunomodulatory signaling to T cells and antigen presenting cells. NK cells are correlated with increased tumor control and better overall patient survival across various types of cancers including non-small cell lung cancer (NSCLC). Despite their promising potential for anti-tumor killing, NK cell function is often diminished within the tumor microenvironment. There are many factors that lead to decreased tumor-infiltrating NK cell killing, including immunoinhibitory factors from tumor cells and resident tissues, acquired …

Multivariate Protein Landscape Of Host Response In Hospitalised Patients With Suspected Infection In The Emergency Department, Pratik Sinha, Et Al.

2020-Current year OA Pubs

Suspected infection requiring hospitalisation has highly heterogenous presentation. Yet, variances in host response and its implications are largely unknown. In this multicentre cohort of 3802 individual patients presenting to the Emergency Department (ED) with suspected infection requiring hospitalisation, we apply uniform manifold approximation and projections and K-means clustering to 29 plasma proteins to identify biologically discrete host response clusters. In this work, we first describe two large clusters, called "Dysregulated" and "Undifferentiated", with abnormal protein concentrations and adverse outcomes in the former. Through further clustering, we identify 4 sub-clusters in the Dysregulated cluster, each with discrete biological signatures, clinical correlates, …

Multi-Ancestral Genome-Wide Association Study Of Clinically Defined Nicotine Dependence Reveals Strong Genetic Correlations With Other Substance Use Disorders And Health-Related Traits, Emma C Johnson, Jared V Balbona, Alexander S Hatoum, David A A Baranger, Louis Fox, Paul W Jeffries, Laura J Bierut, Andrew C Heath, Pamela A Madden, Elliot C Nelson, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement.

METHODS: We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.

RESULTS: We replicated the well-known association at the

CONCLUSIONS: Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics …

The Promise And Peril Of Comparing Fluorescence Lifetime In Biology Revealed By Simulations, Pingchuan Ma, Peter Chen, Scott Sternson, Yao Chen

2020-Current year OA Pubs

Signaling dynamics are crucial in biological systems, and biosensor-based real-time imaging has revolutionized their analysis. Fluorescence lifetime imaging microscopy (FLIM) excels over the widely used fluorescence intensity imaging by allowing the measurement of absolute signal levels independent of sensor concentration. This capability enables the comparison of signaling dynamics across different animals, body regions, and timeframes. However, FLIM's advantage can be compromised by factors like autofluorescence in biological experiments. To address this, we introduce FLiSimBA, a flexible computational framework for realistic

Quantifying Collective Interactions In Biomolecular Phase Separation, Hannes Ausserwöger, Ella De Csilléry, Daoyuan Qian, Georg Krainer, Timothy J Welsh, Tomas Sneideris, Titus M Franzmann, Seema Qamar, Nadia A Erkamp, Jonathon Nixon-Abell, Mrityunjoy Kar, Peter St George-Hyslop, Anthony A Hyman, Simon Alberti, Rohit V Pappu, Tuomas P J Knowles

2020-Current year OA Pubs

Biomolecular phase separation is an emerging theme for protein assembly and cellular organisation. The collective forces driving such condensation, however, remain challenging to characterise. Here we show that tracking the dilute phase concentration of only one component suffices to quantify composition and energetics of multicomponent condensates. Applying this assay to several disease- and stress-related proteins, we find that monovalent ions can either deplete from or enrich within the dense phase in a context-dependent manner. By analysing the effect of the widely used modulator 1,6-hexanediol, we find that the compound inhibits phase separation by acting as a solvation agent that expands …

Revisiting The Effect Of Udenafil On Exercise Performance In Patients With Fontan Circulation: Results Of A Post Hoc Analysis Of The Fuel Trial, David J Goldberg, William B Orr, Et Al.

2020-Current year OA Pubs

BACKGROUND: In the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (Vo

METHODS: Participants were divided into subgroups by baseline predicted peak Vo

RESULTS: Of the 379 participants with paired exercise data, 302 (80%) had a baseline peak Vo

CONCLUSIONS: In this post hoc subgroup analysis, after exclusion of patients with Fontan circulation with near-normal baseline peak Vo

REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT0274115.

Experience-Dependent Intrinsic Plasticity In Layer Iv Of Barrel Cortex At Whisking Onset, Molly C Shallow, Lucy Tian, Bryan T Higashikubo, Hudson Lin, Katheryn B Lefton, Siyu Chen, Joseph D Dougherty, Joe P Culver, Mary E Lambo, Keith B Hengen

2020-Current year OA Pubs

The development of motor control over sensory organs is a critical milestone, enabling active exploration and shaping of the sensory environment. Whether the onset of sensory organ motor control directly influences the development of corresponding sensory cortices remains unknown. Here, we confirm and exploit the late onset of whisking behavior in mice to address this question in the somatosensory system. Using ex vivo electrophysiology, we describe a transient increase in the intrinsic excitability of excitatory neurons in layer IV of the barrel cortex, which processes whisker input, immediately following the onset of active whisking on postnatal days 13 and 14. …

Echocardiographic Assessment Of Pulmonary Hemodynamics And Right Ventricular Performance In Neonatal Murine Hypoxia, Kel Vin Woo, Philip T Levy, Carla J Weinheimer, Amanda L Hauck, Aaron Hamvas, David M Ornitz, Attila Kovacs, Gautam K Singh

2020-Current year OA Pubs

No abstract provided.

Novel Neuroactive Steroid Analogs And Voltage-Dependent Blockers Of Cav3.2 Currents, B372 And Yx23, Are Effective Anti-Nociceptives With Diminished Sedative Properties In Intact Female Mice, Benjamin Volvovitz, Rakib Miah, Kibeom Park, Jae Hun Kim, Raul Vargas, Yuanjiang Xu, Mingxing Qian, Douglas F Covey, Slobodan M Todorovic, Vesna Jevtovic-Todorovic

2020-Current year OA Pubs

Although opioids are effective in treating pain, they cause serious side effects. The use of regional anesthesia, although effective in the perioperative period, may not be suitable if mobility and lack of numbness is desired. Hence, there is a clear need for novel pain therapies. Low-voltage activated (T-type) calcium channels (Ca

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett's Esophagus Development, Ramon U. Jin, Yuanwei Xu, T. Mamie Lih, Yang-Zhe Huang, Toni M. Nittolo, Blake E. Sells, Olivia M. Dres, Jean S. Wang, Qing K. Li, Hui Zhang, Jason C. Mills

2020-Current year OA Pubs

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Informatics At The Frontier Of Cancer Research, Kathleen Noller, Malachi Griffith, Daniel Marcus, Et Al.

2020-Current year OA Pubs

Digitized healthcare data, high-throughput profiling technologies, and data repositories have facilitated the emergence of a new era of cancer research. Each data stream requires specialized analysis methods for interpretation. The data-driven era of cancer research requires the development, enhancement, and sustainment of informatics technology software infrastructure, including fundamental methodology development in artificial intelligence and data science. We review current and emerging informatics technology developments for cancer research and discovery, spanning molecular and cellular characterizations, image analysis, informatics, and therapeutics. Summarizing the diverse methods and applications of informatics throughout cancer research identifies themes and emerging areas for the next generation of …

Integration Of Spatial Protein Imaging And Transcriptomics In The Human Kidney Tracks The Regenerative Potential Of Proximal Tubules, Mahla Asghari, Sanjay Jain, Et Al.

2020-Current year OA Pubs

The organizational principles of nephronal segments are based on anatomical and physiological attributes that are linked to the homeostatic functions of the kidney. Recent molecular approaches have uncovered layers of deeper signatures and states in tubular cells that arise at various time points on the disease trajectory. Here, we introduce an analytical pipeline of multiplexed spatial protein imaging integrated with RNA expression to characterize proximal tubular subpopulations and neighborhoods in human kidney tissue. We demonstrate that, in reference tissue, a large proportion of S1 proximal tubular epithelial cells expresses thymus antigen 1 (THY1), a mesenchymal stromal and stem cell marker …

Highly Potent And Subtype-Selective Sperm-Specific Potassium Channel Slo3 Inhibitors Display High Tissue Exposure In The Murine Female Reproductive Tract, Kayla J Temple, Ping Li, Maximilian D Lyon, Shweta Bhagwat, Leila Asadi, Sophia Li, Ronald Mccarthy, Celia M Santi, Et Al.

2020-Current year OA Pubs

To date, the study of drug exposure and distribution throughout the female reproductive tract has often been overlooked and neglected. Herein, we report the first highly potent and subtype-selective sperm-specific potassium channel 3 (SLO3) inhibitors as a new modality of contraceptives. After extensive

Structural Insights Into Ssna1 Self-Assembly And Its Microtubule Binding For Centriole Maintenance, Lorenzo Agostini, Jason A Pfister, Nirakar Basnet, Jienyu Ding, Rui Zhang, Christian Biertümpfel, Kevin F O'Connell, Naoko Mizuno

2020-Current year OA Pubs

SSNA1 is a fibrillar protein involved in dynamic microtubule remodeling, including nucleation, co-polymerization, and microtubule branching. The underlying molecular mechanism has remained unclear due to a lack of structural information. Here, we determine the cryo-EM structure of C.elegans SSNA-1 at 4.55-Å resolution and evaluate its role in embryonic development. We find that SSNA-1 forms an anti-parallel coiled-coil, with self-assembly facilitated by an overhang of 16 C-terminal residues that form a triple-stranded helical junction. The microtubule-binding region is within the triple-stranded junction, suggesting that self-assembly of SSNA-1 creates hubs for effective microtubule interaction. Genetical analysis elucidates that SSNA-1 deletion significantly reduces …

Structural Basis For Membrane Microdomain Formation By A Human Stomatin Complex, Jack Stoner, Shufang Li, Ziao Fu

2020-Current year OA Pubs

Biological membranes are not just passive barriers-they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 Å cryo-electron microscopy structure of the human Stomatin complex in a native membrane environment. We find that Stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a ~12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits …

Vaccination With Acinetobacter Baumannii Adhesin Abp2d Provides Protection Against Catheter-Associated Urinary Tract Infection, Morgan R Timm, Kevin O Tamadonfar, Taylor M Nye, Jesús Bazán Villicaña, Jerome S Pinkner, Karen W Dodson, Ali H Ellebedy, Scott J Hultgren

2020-Current year OA Pubs

Catheter-associated urinary tract infections (CAUTIs) contribute greatly to the burden of healthcare-associated infections. Acinetobacter baumannii is a Gram-negative bacterium with high levels of antibiotic resistance that is of increasing concern as a CAUTI pathogen. A. baumannii expresses fibrinogen-binding adhesins (Abp1D and Abp2D) that mediate biofilm formation on catheters, which become coated with fibrinogen upon insertion. Here we develop a protein subunit vaccine against the Abp1D and Abp2D receptor binding domains (RBD) and show that vaccination significantly reduces bacterial titers in a female mouse model of CAUTI. We further demonstrate that immunity to Abp2D

Hsp70 Is A Chaperone For Il-33 Activity In Chronic Airway Disease, Omar A. Osorio, Heather E. Raphael, Colin E. Kluender, Ghandi F. Hassan, Lucy S. Cohen, Deborah F. Steinberg, Ella Katz-Kiriakos, Morgan D. Payne, Ethan M. Luo, Jamie L. Hicks, Derek E. Byers, Jennifer Alexander-Brett

2020-Current year OA Pubs

IL-33 is a key driver of type 2 inflammation and implicated in pathology of chronic obstructive pulmonary disease (COPD) and asthma. However, the mechanism for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. We previously reported an airway disease-associated isoform IL-33Δ34 that escapes nuclear sequestration and is tonically secreted from epithelial cells. Here, we describe how this IL-33Δ34 isoform interacts with HSP70 within cells and is targeted to secretory organelles through coordinated binding to phosphatidylserine (PS) and delivered to compartments for unconventional protein secretion (CUPS). Once secreted, extracellular HSP70 (eHSP70) in complex with IL-33Δ34 …

Lipid-Mediated Gating Of A Miniature Mechanosensitive Mscs Channel From Trypanosoma Cruzi, Jingying Zhang, Aashish Bhatt, Grigory Maksaev, Yun Lyna Luo, Peng Yuan

2020-Current year OA Pubs

The mechanosensitive channel of small conductance (MscS) from E. coli (EcMscS) has served as the prevailing model system for understanding mechanotransduction in ion channels. Trypanosoma cruzi, the protozoan parasite causing Chagas disease, encodes a miniature MscS ortholog (TcMscS) critical for parasite development and infectivity. TcMscS contains a minimal portion of the canonical EcMscS fold yet maintains mechanosensitive channel activity, thus presenting a unique model system to assess the essential molecular determinants underlying mechanotransduction. Using cryo-electron microscopy and molecular dynamics simulations, we show that TcMscS contains two short membrane-embedded helices that would not fully cross an intact lipid bilayer. Consequently, drastic …

Artificial Transneurons Emulate Neuronal Activity In Different Areas Of Brain Cortex, Rivu Midya, Ambarish S Pawar, Debi P Pattnaik, Eric Mooshagian, Pavel Borisov, Thomas D Albright, Lawrence H Snyder, R Stanley Williams, J Joshua Yang, Alexander G Balanov, Sergei Gepshtein, Sergey E Savel'ev

2020-Current year OA Pubs

Rapid development of memristive elements emulating biological neurons creates new opportunities for brain-like computation at low energy consumption. A first step toward mimicking complex neural computations is the analysis of single neurons and their characteristics. Here we measure and model spiking activity in artificial neurons built using diffusive memristors. We compare activity of these artificial neurons with the spiking activity of biological neurons measured in sensory, pre-motor, and motor cortical areas of the monkey (male) brain. We find that artificial neurons can operate in diverse self-sustained and noise-induced spiking regimes that correspond to the activity of different types of cortical …

Iodine-Promoted Oxidative Cross-Coupling For The Synthesis Of (E)-2-(3-Oxo-3-Phenylprop-1-En-1-Yl)-3-Phenylquinazolin-4(3 H)-One Via C-H Activation: Development Of Synthetic Tlx Agonists, Lingaiah Maram, Puhan Zhao, Thomas Koelblen, Lamees Hegazy, Thomas P Burris, Bahaa Elgendy

2020-Current year OA Pubs

We report the development of an efficient iodine-promoted oxidative cross-coupling reaction for the synthesis of (

A Rapid, Simple, And Economical Method For The Isolation Of Ribosomes And Translational Machinery For Structural And Functional Studies, Jessey Erath, Danielle Kemper, Elisha Mugo, Alex Jacoby, Elizabeth Valenzuela, Courtney F Jungers, Wandy L Beatty, Yaser Hashem, Marko Jovanovic, Sergej Djuranovic, Slavica Pavlovic Djuranovic

2020-Current year OA Pubs

Ribosomes are RNA-protein complexes essential for protein synthesis and quality control. Traditional methods for ribosome isolation are labor-intensive, expensive, and require a substantial amount of biological material. In contrast, our method, RNA affinity purification using poly-lysine (RAPPL), provides a rapid, simple, and cost-effective alternative applicable to various species and types of starting material (cell lysates, whole cells, organs, or whole organisms). It is also compatible with traditional isolation techniques. Here, we describe the use of RAPPL for rapid isolation, functional screening, and structural analysis of ribosomes and associated factors. We also demonstrate the application of RAPPL in investigating ribosome-associated resistance …

An Ethanol-Induced Loss Of The Lipid Droplet-Associated Segregase Vcp/P97 Leads To Hepatic Steatosis, Sandhya Sen, Shaun Weller, Ryan J Schulze, Donglin Ding, Carol A Casey, Conrad Weihl, Mark A Mcniven

2020-Current year OA Pubs

The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17β13) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor …

Alternative To The Statistical Mass Confusion Of Testing For "No Effect", Josh L Morgan

2020-Current year OA Pubs

In cell biology, statistical analysis means testing the hypothesis that there was no effect. This weak form of hypothesis testing neglects effect size, is universally misinterpreted, and is disastrously prone to error when combined with high-throughput cell biology. The solution is for analysis of measurements to start and end with an interpretation of effect size. In this manuscript, I walk through some of the common critiques of significance testing and how they relate to experimental cell biology. I argue that careful consideration of effect size should be returned to its central position in the planning and discussion of cell biological …

Stem Cell-Derived Corneal Epithelium: Engineering Barrier Function For Ocular Surface Repair, Emily Elizabeth Fresenko, Jian-Xing Ma, Matthew Giegengack, Atalie Carina Thompson, Anthony Atala, Andrew J W Huang, Yuanyuan Zhang

2020-Current year OA Pubs

The cornea, the transparent anterior window of the eye, critically refracts light and protects intraocular structures. Corneal pathologies, including trauma, infection, chemical injury, metabolic diseases, genetic conditions, and age-related degeneration, can lead to significant visual impairment. While penetrating keratoplasty or full-thickness corneal transplantation remains a standard and effective intervention for severe corneal dysfunction, limitations in donor tissue availability and the risk of immunogenic graft rejection necessitate alternative therapeutic strategies. Furthermore, for cases of isolated epithelial disfunction, a full-thickness cornea graft may not be required or effective. This review examines the potential of corneal epithelial constructs derived from autologous stem cells …

Sporadic Als Induced Pluripotent Stem Cell Derived Neurons Reveal Hallmarks Of Tdp-43 Loss Of Function, Jeffrey D Rothstein, Olivia Keeley, Caroline Warlick, Timothy M Miller, Cindy V Ly, Jonathan D Glass, Alyssa N Coyne

2020-Current year OA Pubs

Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same …

Genetic Diversity And Expanded Phenotypes In Dystonia: Insights From Large-Scale Exome Sequencing, Mirja Thomsen, Joel S Perlmutter, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex.

METHODS: Exome sequencing was conducted on 1924 genetically unsolved, mainly late-onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia (n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible.

RESULTS: We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG …

Formation Control Between Leader And Migratory Follower Tissues Allows Coordinated Growth, Toru Kawanishi, Takamichi Sushida, Tony Y-C Tsai, Hiroyuki Takeda, Sean G Megason

2020-Current year OA Pubs

Coordinated growth of multiple tissues is fundamental to shaping our body, but the underlying mechanisms remain underexplored. In zebrafish embryos, midline tissues composed of the notochord, floorplate, and hypochord elongate synchronously with their lengths aligned. We show that floorplate and hypochord cells collectively migrate posteriorly along the nascent notochord extracellular matrix as it extends posteriorly, maintaining the tripartite configuration. Fibroblast growth factor-mediated migration in a spatially graded manner causes cell stretching, which triggers Yap-dependent proliferation and controls floorplate and hypochord growth. Supported by mathematical modeling, we further suggest that their growth is fine-tuned by mechanical tethering to the notochord via …