Biology subjects

Teruel, M. N.

Publications and source records attributed to Teruel, M. N..

9 recordsLinked to original sources

bioRxiv2026

YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells must proliferate to expand the cell population, yet terminal differentiation requires this proliferative state to end. How signaling controls the duration of this proliferative window remains poorly understood. Using adipogenesis and live single-cell imaging of differentiation, cell-cycle, and ERK-activity reporters, we show that YAP and TAZ coordinate progenitor expansion with differentiation commitment by regulating ERK dynamics. YAP/TAZ maintain cells in a fluctuating high-ERK state that promotes proliferation while actively keeping the differentiation driver PPARG below the threshold for irreversible commitment. Crucially, this differentiation block is not explained by proliferation alone: inhibiting CDK4/6 or AKT suppressed proliferation without restoring differentiation, whereas MEK-ERK inhibition restored differentiation even when YAP/TAZ activity remained high. As YAP/TAZ activity decreases, dampened ERK fluctuations trigger PPARG activation. These findings support a self-limiting model in which YAP/TAZ-driven progenitor expansion progressively increases cell density and contact-dependent Hippo signaling, reducing YAP/TAZ activity and terminating the proliferative phase. Consequently, transient YAP/TAZ activation expands the progenitor pool while preserving subsequent differentiation, whereas sustained activation suppresses commitment. Together, these findings identify YAP/TAZ-controlled ERK dynamics as the nexus coordinating progenitor expansion with terminal differentiation and suggest that slower density-dependent Hippo feedback may set the duration of this proliferative window to regulate differentiated cell-number output.

cell biology↗

bioRxiv2026

The beta cell glucocorticoid receptor protects against hyperglycaemia by modulating insulin secretion during glucocorticoid rhythm disruption in mice

Aims/hypothesis: Hyperinsulinaemia is typically viewed as a secondary, compensatory response to insulin resistance or elevated glycaemia. However, we previously found that disrupting the daily glucocorticoid rhythm in mice rapidly increases circulating insulin several-fold while fasting glucose remains normal. This raised the question of what generates and sustains the hyperinsulinaemia. Because glucocorticoids act directly on beta cells through the glucocorticoid receptor (GR), we tested whether beta cell GR is required for this rise in insulin and whether elevated insulin is necessary to maintain glucose homeostasis. Methods: Glucocorticoid rhythms were disrupted in male C57BL/6J mice by subcutaneously implanting corticosterone pellets that raise the trough and lower the peak while maintaining near-physiological mean glucocorticoid exposure, a manipulation we refer to as GC-flattening. Placebo-treated mice served as controls, and high-fat-diet-fed mice provided a metabolic comparison. Beta cell function was assessed by dynamic glucose stimulated insulin secretion and beta cell specific Ca2+ imaging. The requirement for beta cell GR was tested using adult-inducible beta cell specific GR knockout mice, thereby limiting developmental effects of constitutive GR deletion. Combined beta cell and hepatocyte GR knockout mice were used to test the consequences of further reducing systemic insulin availability. Insulin sensitivity and glucose tolerance were assessed in vivo. Insulin clearance was assessed from plasma C-peptide:insulin ratios, direct measurement of the disappearance of intravenously administered human insulin, and hepatic insulin-degrading enzyme abundance and activity. Results: GC-flattening produced rapid, sustained hyperinsulinaemia while blood glucose remained normal, distinct from the more gradual hyperinsulinaemia and hyperglycaemia observed in high-fat-diet-fed mice. Islets from GC-flattened mice retained enhanced insulin secretion and Ca2+ responses to glucose after isolation, indicating a persistent increase in beta cell glucose responsiveness. During GC-flattening, beta cell GR deletion reduced cumulative circulating insulin exposure by approximately 40% (p < 0.001) and worsened glycaemic control despite similar or greater insulin sensitivity, demonstrating that the GR-dependent rise in insulin helps maintain glucose homeostasis. Direct measurement on Day 3 confirmed reduced insulin clearance in GC-flattened mice. This was accompanied by a reduced plasma C-peptide-to-insulin ratio and decreased hepatic insulin-degrading enzyme abundance and activity. Further lowering circulating insulin by combined beta cell and hepatocyte GR deletion worsened glycaemic control further. Conclusions/interpretation: Disruption of glucocorticoid rhythmicity directly initiates hyperinsulinaemia by enhancing glucose-stimulated insulin secretion through beta cell GR signalling and by reducing insulin clearance. The resulting increase in insulin is required to maintain glucose homeostasis, demonstrating that hyperinsulinaemia can be an early adaptive response to altered endocrine timing rather than simply a consequence of insulin resistance or hyperglycaemia.

physiology↗

bioRxiv2025

High fat diet but not glucocorticoid-induced obesity results in fatty liver

Chronic stress, modeled by flattened circadian glucocorticoid (GC) oscillations, is increasingly implicated in obesity. We investigated the underlying mechanisms by disrupting GC rhythms in mice, elevating normally low GC levels during the rest period. This disruption induced substantial obesity, comparable to a 60% high-fat diet (HFD), with additive effects on fat mass, suggesting distinct mechanisms driving adiposity. Despite similar adiposity, GC-flattening and HFD produced profoundly different metabolic outcomes. HFD led to hepatic steatosis and elevated fasting glucose/fatty acid levels, reflecting typical diet-induced dysfunction. In contrast, GC-flattening maintained low fasting glucose/fatty acid levels and prevented hepatic lipid accumulation, with increased adiposity driven by a shift of glucose uptake from muscle to fat and suppression of lipolysis. This reveals a previously unrecognized mechanism of obesity development where excess fat accumulation occurs independently of the mechanisms driving metabolic dysfunction observed in diet-induced obesity. The dissociation between obesity and metabolic dysfunction in GC-flattening challenges the view that increased adiposity and persistent hyperinsulinemia inevitably leads to fatty liver disease. Understanding this pathway opens avenues for novel therapeutic interventions targeting stress-related metabolic disorders.

physiology↗

bioRxiv2025

Inactivation of CDK4/6, CDK2, and ERK in G1-phase triggers differentiation commitment

Terminal cell differentiation, a process vital for tissue development and regeneration where progenitor cells acquire specialized functions and permanently exit the cell cycle, is still poorly understood at the molecular level. Using live-cell imaging and adipogenesis as a model, we demonstrate that the initial stage involves a variable number of cell divisions driven by redundant CDK4/6 or CDK2 activation.. Subsequently, a delayed decrease in cyclin D1 and an increase in p27 levels leads to the attenuation of CDK4/6 and CDK2 activity. This results in G1 lengthening and the induction of PPARG, the master regulator of adipogenesis. PPARG then induces p21, and later p18, culminating in the irreversible inactivation of CDK4/6 and CDK2, and thus, permanent cell cycle exit. However, contrary to expectation, CDK inactivation alone is not sufficient to trigger commitment to differentiation and functional specialization; ERK inactivation is also required. Our study establishes that the coordinated activation and subsequent delayed inactivation of CDK4/6, CDK2, and ERK are crucial determinants for irreversible cell cycle exit and differentiation commitment in terminal cell differentiation.

cell biology↗

bioRxiv2024

Transient proliferation by reversible YAP-mediated increase of the cyclin D1/p27 ratio

Hippo-YAP signaling orchestrates epithelial tissue repair and is therefore an attractive target in regenerative medicine. Yet it is unresolved how YAP integrates with mitogen signaling and contact inhibition to control the underlying transient proliferative response. Here we show that reduced contact inhibition, increased mitogen signaling, and YAP-TEAD activation converge on increasing the nuclear cyclin D1/p27 protein ratio during G1 phase, towards a threshold ratio that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio indirectly, in concert with mitogen signaling, by increasing EGFR and other receptors that signal primarily through ERK. After a delay, contact inhibition suppresses YAP activity which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Increasing YAP activity by ablating the suppressor Merlin/NF2 reveals a balancing mechanism in which YAP suppression and contact inhibition of proliferation can be recovered but only at higher local cell density. Thus, critical for tissue repair, robust proliferation responses result from the YAP-induced and receptor-mediated prolonged increase in the cyclin D1/p27 ratio, which is only reversed by delayed suppression of receptor signaling after contact inhibition of YAP.

cell biology↗

bioRxiv2022

A dynamic HIF1alpha-PPARgamma circuit controls a paradoxical adipocyte regulatory landscape

Hypoxia-induced upregulation of HIF1 triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1 closely interacts with PPAR{gamma}, the master regulator of adipocyte differentiation and lipid accumulation, but there are conflicting results how this co-regulation controls the excessive lipid accumulation that drives adipocyte dysfunction. Using single-cell imaging and modeling, we find that, surprisingly, HIF1 both promotes and represses lipid accumulation during adipogenesis. We show that the opposing roles of HIF1 are isolated from each other and depend on when HIF1 increases relative to the positive-feedback mediated upregulation of PPAR{gamma} that drives adipocyte differentiation. A theoretical model incorporating our findings resolves conflicting prior results and suggests that three network nodes before and after the isolation step have to be synergistically targeted in therapeutic strategies to revert hypoxia-mediated adipose tissue dysfunction in obesity. TeaserA systems biology approach detangles the effect of hypoxic and adipogenic regulators on lipid accumulation in adipocytes.

systems biology↗

bioRxiv2019

Stochastic and coincident control of terminal cell differentiation and cell cycle exit

Terminal differentiation is essential for the development and maintenance of tissues in all multi-cellular organisms and is associated with a permanent exit from the cell cycle. Failure to permanently exit the cell cycle can result in cancer and disease. However, the molecular mechanisms and timing that coordinates differentiation commitment and cell cycle exit are not yet understood. Here using adipogenesis as a model system to track differentiation commitment in live cells, we show that a rapid switch mechanism engages exclusively in G1 to trigger a simultaneous commitment to differentiate and permanently exit from the cell cycle. We identify a signal integration mechanism whereby the strengths of both mitogen and differentiation stimuli control a molecular competition between cyclin D1 and PPARG-induced expression of the CDK inhibitor p21 which in turn regulates if and when the differentiation switch is triggered and when the proliferative window closes. In this way, the differentiation control system is able to couple mitogen and differentiation stimuli to sustain a long-term balance between terminally differentiating cells and maintaining the progenitor cell pool, a parameter of critical importance for enabling proper development of tissue domains and organs. HIGHLIGHTSO_LIProgenitor cells both commit to terminally differentiate and permanently exit the cell cycle at a precise time in G1 as a result of a competition process that can last over multiple cell cycles. C_LIO_LIPositive-feedback driven expression of PPARG and the parallel induction of p21 triggers a rapid commitment to terminally differentiate and then maintains a postmitotic adipocyte state. C_LIO_LIOpposing mitogen and adipogenic signals are funneled into a molecular competition in G1 phase that controls if and when cells commit to differentiate, which in turn regulates the number of differentiated cells produced while allowing for the maintenance of sufficient progenitor cells. C_LI

cell biology↗

bioRxiv2018

Transcription factor dynamics reveals a circadian code for fat cell differentiation

Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern during stress and disease correlates with increased fat mass and obesity in humans, raising the intriguing question of how hormone secretion dynamics affect the process of adipocyte differentiation. By using live, single-cell imaging of the key adipogenic transcription factors CEBPB and PPARG, endogenously tagged with fluorescent proteins, we show that pulsatile circadian hormone stimuli are rejected by the adipocyte differentiation control system, leading to very low adipocyte differentiation rates. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify the mechanism of how hormone oscillations are filtered as a combination of slow and fast positive feedback centered on PPARG. Furthermore, we confirm in mice that flattening of daily glucocorticoid oscillations significantly increases the mass of subcutaneous and visceral fat pads. Together, our study provides a molecular mechanism for why stress, Cushings disease, and other conditions for which glucocorticoid secretion loses its pulsatility can lead to obesity. Given the ubiquitous nature of oscillating hormone secretion in mammals, the filtering mechanism we uncovered may represent a general temporal control principle for differentiation.\n\nHIGHLIGHTO_LIWe found that the fraction of differentiated cells is controlled by rhythmic and pulsatile hormone stimulus patterns.\nC_LIO_LITwelve hours is the cutoff point for daily hormone pulse durations below which cells fail to differentiate, arguing for a circadian code for hormone-induced cell differentiation.\nC_LIO_LIIn addition to fast positive feedback such as between PPARG and CEBPA, the adipogenic transcriptional architecture requires added parallel slow positive feedback to mediate temporal filtering of circadian oscillatory inputs\nC_LI

cell biology↗

bioRxiv2018

Expression variation and covariation impair analog and enable binary signaling control

Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25% between cells. This high variation enables population-level regulation of cell functions but abolishes accurate single-cell signal transmission. Here we measure cell-to-cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5-15%, compatible with accurate single-cell transmission. Furthermore, we show that MEK and ERK expression covary which improves controllability of the fraction of cells that activate bimodal ERK signaling, arguing that covariation has a role in facilitating population-level control of binary cell-fate decisions. Together, our experimental and model data argues for a control principle whereby low covariation limits signaling noise for accurate control analog single-cell signaling. In contrast, increased covariation widens the stimulus-range over which external inputs can regulate binary cell activation, thereby enabling accurate control of the fraction of activated cells at the population level.

systems biology↗