Biology subjects

Ramirez, A.

Publications and source records attributed to Ramirez, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks

We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased A{beta} levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/PLC{gamma}2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLC{gamma}2 downregulation could increase AD risk by impairing synaptic functions and increasing the A{beta} levels and Tau phosphorylation in neurons.

neuroscience↗

bioRxiv2023

Diagnostic images for mild cognitive impairment reveal biomarker status and abnormal scene processing

Research on the impairment of episodic memory in Alzheimers disease often focuses on the processes of memory rather than the content of the specific images being remembered. We recently showed that patients with mild cognitive impairment (MCI), Stage 3 of Alzheimers disease, can memorize certain images quite well, suggesting that episodic memory is not uniformly impaired. Certain images, on the other hand, could not be memorized by MCI patients and were instead diagnostic for distinguishing MCI from healthy older adults. In this study, we investigate whether poor memory for diagnostic images is related to impaired neural processing in specific brain regions due to Alzheimers biomarker pathology. 64 healthy controls and 48 MCI participants in the DELCODE dataset performed a visual scene memory task during fMRI, with CSF Alzheimers disease biomarker data collected (i.e., amyloid and tau biomarkers). We found that diagnostic images have larger behavior-biomarker correlations for total tau, phospho-tau, A{beta}42/A{beta}40, A{beta}42/phospho-tau compared to non-diagnostic images, suggesting that memory for these specific images are more affected by Alzheimers disease pathology. The fMRI data revealed an interaction effect between group membership (healthy control / MCI) and image diagnosticity (diagnostic / non-diagnostic scene images), with MCI participants having higher activation in scene processing regions (parahippocampal place area, retrosplenial cortex and occipital place area) for diagnostic images than non-diagnostic images. In contrast, healthy controls showed no differences in processing between diagnostic and non-diagnostic images. These results suggest that MCI individuals may engage in inefficiently heightened encoding activation for these diagnostic images. Our results show that special "diagnostic" images exist that can reveal amyloid and tau pathology and differences in neural activity in scene regions.

neuroscience↗

bioRxiv2023

Epigenome-wide profiling in the dorsal raphe nucleus highlights cell-type-specific changes in TNXB in Alzheimer's disease

Recent studies have demonstrated that the dorsal raphe nucleus (DRN) is among the first brain regions affected in Alzheimers disease. Hence, in this study we conducted the first comprehensive epigenetic analysis of the DRN in AD, targeting both bulk tissue and single isolated cells. The Illumina Infinium MethylationEPIC BeadChip array was used to analyze the bulk tissue, assessing differentially modified positions (DMoPs) and regions (DMoRs) associated with Braak stage. The strongest Braak stage-associated DMoR in TNXB was targeted in a second patient cohort utilizing single laser-capture microdissected serotonin-positive (5-HT+) and -negative (5-HT-) cells isolated from the DRN. Our study revealed previously identified epigenetic loci, including TNXB and PGLYRP1, and novel loci, including RBMXL2, CAST, GNAT1, MALAT1, and DNAJB13. Strikingly, we found that the methylation profile of TNXB depends both on disease phenotype and cell type analyzed, emphasizing the significance of single cell(-type) neuroepigenetic studies in AD.

neuroscience↗

bioRxiv2023

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 {+/-} 6.09 years; 48.7% female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memorys mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95% confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated - and, thus, explained - that association (95% CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

neuroscience↗

bioRxiv2023

Identification of novel buffering mechanisms in aortic arch artery development and congenital heart disease.

RationaleThe resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease (CHD) arising from defective morphogenesis of pharyngeal arch arteries (PAA) and their derivatives. ObjectiveTo uncover mechanisms underlying the robustness of PAA morphogenesis. Methods and ResultsThe second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived ECs is regulated by VEGFR2 and Tbx1. Remarkably, when SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated three-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of one VEGFR2 allele (VEGFR2SHF-HET) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (VEGFR2SHF-KO) abolishes it. The decrease in SHF-derived ECs in VEGFR2SHF-HET and VEGFR2SHF-KO embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in VEGFR2SHF-KO mutants. Blocking the compensatory response in VEGFR2SHF-KO mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in Tbx1+/- embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and CHD. Tbx1 regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner. ConclusionsOur studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling. Nonstandard Abbreviations and Acronyms in Alphabetical OrderCHD - congenital heart disease; ECs - endothelial cells; IAA-B - interrupted aortic arch type B; PAA - pharyngeal arch arteries; RERSA - retro-esophageal right subclavian artery; SHF - second heart field; VEGFR2 - Vascular endothelial growth factor receptor 2.

developmental biology↗

bioRxiv2023

Canary in the Forest? Tree mortality and canopy dieback of western redcedar linked to drier and warmer summer conditions

Tree mortality and partial canopy dieback are increasing in many forest ecosystems from unfavorable climate conditions. Examining how tree growth and mortality are affected by climate variability can help identify proximate causes of tree mortality and canopy dieback. We investigated anomalously high mortality rates and partial canopy dieback of western redcedar (Thuja plicata, WRC), a culturally, ecologically, and economically important species in the Pacific Northwest (USA), using tree-ring methods. We sampled trees in three tree status groups--no canopy dieback, partial canopy dieback, and trees that died (0-30 years ago)--from 11 sites in coastal (maritime climate) and interior (continental climate) populations of WRC trees. In our study, WRC tree mortality was portended by on average 4-5 years of declining radial growth. Warmer and drier climate conditions in May and June that extend the annual July-September dry season reduced radial growth in 9 of 11 sites (1975-2020). Defining drought events as warm, dry May-June climate, we found that WRC trees recovered radial growth to pre-drought rates within three years when post-drought climate conditions were average or cooler and wetter than average. However, radial growth recovery from drought was slower or absent when conditions were warmer and drier during the post-drought recovery period, which appeared to lead to the widespread mortality event across coastal populations. Annually resolved tree mortality in coastal populations predominately occurred in 2017-2018 (80% of sampled trees) and coincided with exceedingly hot temperatures and the longest regionally dry period for May to September (1970-2020). In interior populations, tree mortality was associated with warmer, drier conditions from August to September. Our findings forewarn that a warming climate and more frequent and severe seasonal droughts will likely increase the vulnerability of WRC to canopy dieback and mortality and possibly other drought-sensitive trees in one of the worlds largest carbon sinks.

ecology↗

bioRxiv2022

Fanca and p53 genes cooperate to suppress oral SCC in transgenic mice

Fanconi anemia (FA) patients frequently develop oral squamous cell carcinoma (OSCC). This cancer in FA patients is diagnosed within the first 3-4 decades of life, very often preceded by lesions that suffer a malignant transformation. In addition, they respond poorly to current treatments due to toxicity or multiple recurrences. Translational research of new chemopreventive agents and therapeutic strategies has been unsuccessful partly due to scarcity of disease models or failure to fully reproduce the disease. Here we report that Fanca gene knockout mice (Fanca-/-) frequently display pre-malignant lesions in the oral cavity. Moreover, when these animals were crossed with animals having conditional deletion of Trp53 gene in oral mucosa (K14cre;Trp53F2-10/F2-10), they spontaneously developed OSCC with a high penetrance and a median latency of less than ten months. Tumors were well differentiated and expressed markers of squamous differentiation, such as keratins K5 and K10. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and Fanca-/-;K14cre;Trp53F2-10/F2-10 mice constitute the first animal model of spontaneous OSCC in FA.

cancer biology↗

bioRxiv2022

Multiple particle tracking using PEGylated nanoparticles reveals lymph node is riddled with heterogeneous pores smaller than reported and interstitial tissue material properties vary by lymph node location

Lymph nodes (LNs) are highly structured lymphoid organs that compartmentalize B and T cells in the outer cortex and inner paracortex, respectively, and are supported by a collagen-rich reticular network. Tissue material properties like viscoelasticity and diffusion of materials within extracellular spaces and their implications on cellular behavior and therapeutic delivery have been a recent topic of investigation. Here, we developed a nanoparticle system to investigate the rheological properties, including pore size and viscoelasticity, through multiple particle tracking (MPT) combined with LN slice cultures. Dense coatings with polyethylene glycol (PEG) allow nanoparticles to diffuse within the LN extracellular spaces. Despite differences in function in B and T cell zones, we found that extracellular tissue properties and mesh spacing do not change significantly in the cortex and paracortex, though nanoparticle diffusion was slightly reduced in B cell zones. Interestingly, our data suggest that LN pore sizes are smaller than the previously predicted 10 - 20 m, with pore sizes ranging from 500 nm - 1.5 m. Our studies also confirm that LNs exhibit viscoelastic properties, with an initial solid-like response followed by stress-relaxation at higher frequencies. Finally, we found that nanoparticle diffusion is dependent on LN location, with nanoparticles in skin draining LNs exhibiting a higher diffusion coefficient and pore size compared to mesenteric LNs. Our data shed new light onto LN interstitial tissue properties, pore size, and define surface chemistry parameters required for nanoparticles to diffuse within LN interstitium. Our studies also provide both a tool for studying LN interstitium and developing design criteria for nanoparticles targeting LN interstitial spaces. AbbreviationsLNs, FBS, EDC, NHS, ECM, PEG

immunology↗

bioRxiv2022

Individualized Gaussian Process-based Prediction of Memory Performance and Biomarker Status in Ageing and Alzheimer's disease

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as informative covariates, vascular risks, brain activity, neuropsychological test etc.,) might provide useful predictions of clinical outcomes during progression towards Alzheimers disease (AD). The Bayesian approach aims to provide a trade-off by employing relevant features combinations to build decision support systems in clinical settings where uncertainties are relevant. We tested the approach in the MRI data across 959 subjects, aged 59-89 years and 453 subjects with available neuropsychological test scores and CSF biomarker status (amyloid-beta (A{beta})42/40 & and phosphorylated tau (pTau)) from a large sample multi-centric observational cohort (DELCODE). In order to explore the beneficial combinations of information from different sources, we presented a MRI-based predictive modelling of memory performance and CSF biomarker status (positive or negative) in the healthy ageing group as well as subjects at risk of Alzheimers disease using a Gaussian process multikernel framework. Furthermore, we systematically evaluated predictive combinations of input feature sets and their model variations, i.e. (A) combinations of brain tissue classes and feature type (modulated vs. unmodulated), choices of filter size of smoothing (ranging from 0 to 15 mm full width at half maximum), and image resolution (1mm, 2mm, 4mm and 8mm); (B) incorporating demography and covariates (C) the impact of the size of the training data set (i.e., number of subjects); (D) the influence of reducing the dimensions of data and (E) choice of kernel types. Finally, the approach was tested to reveal individual cognitive scores at follow-up (up to 4 years) using the baseline features. The highest accuracy for memory performance prediction was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF-biomarkers explaining 57% of outcome variance in out of sample predictions. The best accuracy for A{beta}42/40 status classification was achieved for combination demographics, ApoE4 and memory score while usage of structural MRI improved the classification of individual patients pTau status.

neuroscience↗

bioRxiv2022

Belgian endive-derived biostimulants promote shoot and root growth in vitro.

Recovering biostimulant compounds from by-products of crops is a promising strategy to add value, enhance sustainability, and increase the environmental safety of the agricultural production chain. Here, we report consistent root and shoot growth-stimulating bioactivity present in water-based extracts from Belgian endive forced roots (Cichorium intybus var. foliosum) over two consecutive harvest years. The shoot and the primary root of in vitro cultivated Arabidopsis thaliana treated with Belgian endive extract were about 30% increased in size compared to plants grown under control conditions. The ornamental species Plectranthus esculentus also showed enhanced in vitro shoot and root growth, suggesting bioactivity on a broad range of species. Fractionation of the Belgian endive extracts into aqueous and organic subfractions coupled with bio-activity measurements showed that the principal root and shoot growth-promoting ingredients are primarily water-soluble. NMR-based characterization of the bioactive aqueous fractions revealed the presence of pre-dominantly sugars and organic acids. Malate and sugars were abundant and common to all water fractions, suggesting these molecules contributed to the growth stimulation phenotype. The findings indicate that Belgian endive roots are a source for the development of organic waste-derived biostimulants with potential for application in tissue culture and putatively for soil-grown crop production.

plant biology↗

bioRxiv2021

Copper signaling promotes proteostasis and animal development via allosteric activation of ubiquitin E2D conjugases

Nutrient copper supply is critical for cell growth and differentiation, and its disturbance is associated with major pathologies including cancer and neurodegeneration. Although increasing copper bioavailability in late Precambrian facilitated emergence of novel cuproproteins, their intricate regulation by this essential trace element remains largely cryptic. We found that subtle rises in cellular copper strikingly increase polyubiquitination and accelerate protein degradation within 30 minutes in numerous mammalian cell lines. We track this surprising observation to allostery induced in the UBE2D ubiquitin conjugase clade through a conserved CXXXC sub-femtomolar-affinity Cu+ binding motif. Thus, physiologic fluctuation in cytoplasmic Cu+ is coupled to the prompt degradation of UBE2D protein targets, including p53. In Drosophila harboring a larval-lethal knockdown of the nearly identical fly orthologue UbcD1, complementation with human UBE2D2 restored near-normal development, but mutation of its CXXXC Cu+ binding motif profoundly disrupted organogenesis. Nutrient Cu+ emerges as a trophic allosteric modulator of UBE2D activity through a structural motif whose evolution coincides with animal multicellularity. One Sentence SummaryModulation of nutrient copper impacts protein turnover and animal morphogenesis through conserved allostery of ubiquitin E2D conjugases. HilightsO_LINutrient copper supply is critical for cell growth and differentiation C_LIO_LIThe E2D clade of ubiquitin conjugases contains a sub-femtomolar-affinity Cu+ binding motif C_LIO_LIAllosteric activation by Cu+ markedly accelerates protein polyubiquitination C_LIO_LIThis sensor couples physiologic fluctuations in cytoplasmic Cu+ with the degradation rate of E2D targets, including p53 C_LIO_LIThis metazoan signaling mechanism is critical for drosophila morphogenesis C_LI In BriefConserved allostery of ubiquitin E2D conjugases links nutrient copper signaling to protein degradation and animal morphogenesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/431211v2_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@17009fforg.highwire.dtl.DTLVardef@a07f8eorg.highwire.dtl.DTLVardef@11664c7org.highwire.dtl.DTLVardef@1327ab7_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

biochemistry↗

bioRxiv2020

Evaluation of a polymeric composite bone filler scaffold for local antibiotic delivery to prevent Staphylococcus aureus infection in a contaminated bone defect

We previously reported the development of an osteogenic bone filler scaffold consisting of degradable polyurethane (dPU), nano-sized hydroxyapatite (nHA), and decellularized bovine bone particles (DBP). In this report we describe the results of studies aimed at evaluating the use of this scaffold as a means of local antibiotic delivery for the prevention of infection in a segmental bone defect contaminated with Staphylococcus aureus. We evaluated two different scaffold formulations that contained the same components in the same ratios but differed from each other with respect to overall porosity and therefore surface area. Studies done with vancomycin, daptomycin, and gentamicin confirmed that antibiotic uptake was concentration dependent and that increased porosity was correlated with increased uptake and prolonged release of all three antibiotics. Vancomycin could be passively loaded into either scaffold formulation in an amount sufficient to prevent infection, as evidenced by the complete eradication of viable bacteria from the surgical site of most animals in a rabbit model of a contaminated mid-radial segmental bone defect. Even in those few cases in which complete eradication was not achieved, the number of viable bacteria present in the bone was significantly reduced comparison to untreated controls. There was also no radiographic evidence of osteomyelitis in any rabbit treated with vancomycin-loaded scaffold. Microcomputed tomography (CT) of bone defects up to 84 days of exposure to scaffolds with and without vancomycin also demonstrated that the addition of vancomycin even in the highest concentration did not significantly diminish the osteogenic properties of either scaffold formulation. Together, these results demonstrate the potential utility of our bone regeneration scaffold for local antibiotic delivery.

microbiology↗

bioRxiv2020

Divergence in a stress-associated gene regulatory network underlies differential growth control in the Brassicaceae family

The phytohormone abscisic acid (ABA) is a central regulator of acclimation during environmental stress. While some plants exhibit tremendous stress resilience, it has been unclear whether differences in ABA response underlie such adaptations. Here we establish a cross-species gene regulatory network (GRN) for ABA to identify broadly conserved, core components of the ABA signaling network and peripheral pathways exhibiting species-specific connectivity. Genes that are broadly conserved in the network share promoter architecture and patterns of gene expression. Networks associated with growth hormones exhibited highly divergent wiring of their ABA network leading to changes in the physiological outcome of signaling. Together our study provides a model for understanding how GRN subcircuits deploy different growth regulatory states across ecologically diverse species. One Sentence SummaryComparative studies reveal core and peripheral stress-mediated gene networks driving divergent growth control in plants.

plant biology↗

bioRxiv2020

Modularity and neural coding from a brainstem synaptic wiring diagram

How much can connectomes with synaptic resolution help us understand brain function? An optimistic view is that a connectome is a major determinant of brain function and a key substrate for simulating a brain. Here we investigate the explanatory power of connectomics using a wiring diagram reconstructed from a larval zebrafish brainstem. We identify modules of strongly connected neurons that turn out to be specialized for different behavioral functions, the control of eye and body movements. We then build a neural network model using a synaptic weight matrix based on the reconstructed wiring diagram. This leads to predictions that statistically match the neural coding of eye position as observed by calcium imaging. Our work shows the promise of connectome-based brain modeling to yield experimentally testable predictions of neural activity and behavior, as well as mechanistic explanations of low-dimensional neural dynamics, a widely observed phenomenon in nervous systems.

neuroscience↗

bioRxiv2020

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis.

Sepsis is a serious syndrome characterised by a dysregulated systemic inflammatory response. Here we have analysed the role and the therapeutic potential of Granzyme A (GzmA) in the pathogenesis of peritoneal sepsis using the Cecal Ligation and Puncture (CLP) polymicrobial sepsis model and samples from humans undergoing abdominal sepsis. Elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen indicating that GzmA has no role in bacterial control. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNF. Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis, and suggest that it could be targeted for treatment of this severe pathology.

immunology↗

bioRxiv2020

Multi-Omic Analysis Reveals Cannabidiol Disruption of Cholesterol Homeostasis in Human Cell Lines

The non-psychoactive cannabinoid, cannabidiol (CBD), is FDA-approved for treatment of two drug-resistant epileptic disorders, and is seeing increased use among the general public, yet the mechanisms that underlie its therapeutic effects and side-effect profiles remain unclear. Here, we report a systems-level analysis of CBD action in human cell lines using temporal multi-omic profiling. FRET-based biosensor screening revealed that CBD treatment resulted in a sharp rise in cytosolic calcium, and activation of AMPK and ERK kinases in human keratinocyte and neuroblastoma cell lines. CBD treatment led to alterations in the abundance of metabolites, mRNA transcripts, and proteins consistent with activation of cholesterol biosynthesis, transport and storage. We found that CBD rapidly incorporated into cellular membranes and altered cholesterol chemical activity, suggesting direct perturbation of cholesterol-dependent membrane properties. CBD treatment induced apoptosis in a dose-dependent manner in multiple human cell lines, which was rescued by inhibition of cholesterol synthesis, and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.

systems biology↗

bioRxiv2020

Cell-ECM interactions play distinct and essential roles at multiple stages during the development of the aortic arch arteries

RationaleDefects in the morphogenesis of the 4th pharyngeal arch arteries (PAAs) give rise to lethal birth defects. Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease. ObjectiveCell-ECM interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery (AAA) and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin 5{beta}1 and fibronectin (Fn1) expressed in the Isl1 lineages regulate PAA formation. The objective of these studies was to investigate cellular mechanisms by which integrin 5{beta}1 and Fn1 regulate AAA morphogenesis. Methods and ResultsUsing temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and populate pharyngeal arch mesenchyme between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches become organized into a uniform plexus of small blood vessels, which becomes remodeled into the PAAs between 31 - 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on pharyngeal ECM microenvironment extrinsic to the endothelium. Conditional ablation of integrin 5{beta}1 or Fn1 in the Isl1 lineages showed that signaling by the ECM regulates AAA morphogenesis at multiple steps: 1) the recruitment of the SHF-derived ECs into the pharyngeal arches, 2) the remodeling of the uniform EC plexus in the 4th arches into the PAAs; and 3) differentiation of neural crest-derived cells abutting the PAA endothelium into vascular smooth muscle cells. ConclusionsPAA formation is a multi-step process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the AAA and its major branches. Cell-ECM interactions regulated by integrin 5{beta}1 and Fn1 play essential roles at each of these developmental stages.

developmental biology↗

bioRxiv2019

Learning temporal integration from internal feedback

There has been much focus on the mechanisms of temporal integration, but little on how circuits learn to integrate. In the adult oculomotor system, where a neural integrator maintains fixations, changes in integration dynamics can be driven by visual error signals. However, we show through dark-rearing experiments that visual inputs are not necessary for initial integrator development. We therefore propose a vision-independent learning mechanism whereby a recurrent network learns to integrate via a teaching signal formed by low-pass filtered feedback of its population activity. The key is the segregation of local recurrent inputs onto a dendritic compartment and teaching inputs onto a somatic compartment of an integrator neuron. Model instantiation for oculomotor control shows how a self-corrective teaching signal through the cerebellum can generate an integrator with both the dynamical and tuning properties necessary to drive eye muscles and maintain gaze angle. This bootstrap learning paradigm may be relevant for development and plasticity of temporal integration more generally. Highlights- A neuronal architecture that learns to integrate saccadic commands for eye position. - Learning is based on the recurrent dendritic prediction of somatic teaching signals. - Experiment and model show that no visual feedback is required for initial integrator learning. - Cerebellum is an internal teacher for motor nuclei and integrator population.

neuroscience↗