Extracellular Inputs Research Articles

Food for thought: Nutrient metabolism controlling early T cell development.

T cells develop in the thymus by expressing a diverse repertoire of either αβ- or γδ-T cell receptors (TCR). While many studies have elucidated how TCR signaling and gene expression control T cell ontogeny, the role of nutrient metabolism is just emerging. Here, we discuss how metabolic reprogramming and nutrient availability impact the fate of developing thymic T cells. We focus on how the PI3K/mTOR signaling mediates various extracellular inputs and how this signaling pathway controls metabolic rewiring during highly proliferative and anabolic developmental stages. We highlight the role of the hexosamine biosynthetic pathway that generates metabolites that are utilized for N- and O-linked glycosylation of proteins and how it impacts TCR expression during T cell ontogeny. We consider the dichotomy in metabolic needs during αβ- versus γδ-T cell lineage commitment as well as how metabolism is also coupled to molecular signaling that controls cell fate.

Lineage-specific CDK activity dynamics characterize early mammalian development.

Cyclin-dependent kinases (CDK) are key regulatory enzymes that regulate proliferation dynamics and cell fate in response to extracellular inputs. It remains largely unknown how CDK activity fluctuates and influences cell commitment in vivo during early mammalian development. Here, we generated a transgenic mouse model expressing a CDK kinase translocation reporter (KTR) that enabled quantification of CDK activity in live single cells. By examining pre- and post-implantation mouse embryos at different stages, we observed a progressive decrease in CDK activity in cells from the trophectoderm (TE) prior to implantation. This drop correlated with the establishment of an FGF4-dependent signaling gradient through the embryonic-abembryonic axis. Furthermore, we showed that CDK activity levels do not determine cell fate decisions during pre-implantation development. Finally, we uncovered the existence of conserved regulatory mechanisms in mammals by revealing lineage-specific regulation of CDK activity in TE-like human cells.

Abstract 292: Cell non-autonomous downregulation of the tumor suppressor DAB2IP in the cancer microenvironment: Molecular mechanism and biological implications

Abstract Background and Purpose: The tumor suppressor DAB2IP is a cytoplasmic Ras-GAP and an adaptor protein that restrains oncogenic signaling by extracellular inputs, contributing to modulate the dynamic crosstalk established between tumor cells and their stromal compartment. In human malignancies, DAB2IP is frequently disabled by epigenetic and post-transcriptional means. DAB2IP loss-of-function in cancer cells promotes their aberrant proliferation, dissemination, and tumor-promoting inflammation, potentially favor progression of tumors. Intriguingly, endothelial-specific DAB2IP depletion in mouse models fosters the formation of a pro-metastatic niche, implicating that also the loss-of-function of DAB2IP in stromal cells might dramatically impact cancer progression. We previously found that the secretome of prostate cancer cells reduced DAB2IP levels in non-transformed prostate epithelial cell lines, and in primary endothelial cells, thereby fostering their proliferation, migration and expression of angiogenesis markers. Accordingly, cell non-autonomous DAB2IP inactivation in the stromal compartment may reprogram the response to paracrine and autocrine signals, thus supporting a tumor-promoting behavior; however, molecular basis and clinical implication of this phenomenon await clarification. Materials and Methods: We used conditioned medium (CM) from prostate (PCa) and breast (BCa) cancer cell lines, to study its effects in mediating DAB2IP downregulation and in inducing tumor-associated phenotypes in endothelial cell and fibroblasts. Through multiple approaches, we isolated extracellular vesicles from PCa and BCa conditioned media, to test their involvement in mediating DAB2IP downregulation in recipient cells. Finally, we used cancer cells’CM or specific siRNAs to study the consequence of DAB2IP loss in fibroblasts. Results: The treatment with CM from PCa and BCa cells induces DAB2IP downregulation in immortalized and in primary fibroblasts, and in endothelial cells. Analysis of DAB2IP levels in primary fibroblasts from PCa and BCa surgical samples confirmed differential expression of DAB2IP protein in normal vs. tumor-associated fibroblasts. Exploring the biochemical nature of extracellular signals involved in DAB2IP downregulation by cancer cells’ CM, we found that DAB2IP inhibition in recipient cells is partially mediated by miR-149-3p contained in extracellular vesicles. Finally, we found that DAB2IP reduction potentiates fibroblasts proliferation and invasion, facilitates gel contraction and extracellular matrix remodeling, and fosters expression of markers of activated fibroblasts. Conclusions: Together, these data support the hypothesis that cancer cells can modulate DAB2IP levels in nearby stromal cells, pushing them to acquire a metastasis-supporting phenotypes. Citation Format: Arianna Bellazzo, Rossella De Florian Fania, Chiara Agostinis, Roberta Bulla, Ilenia Segatto, Barbara Belletti, Vito G. D’Agostino, Ian M. Bonapace, Licio Collavin. Cell non-autonomous downregulation of the tumor suppressor DAB2IP in the cancer microenvironment: Molecular mechanism and biological implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 292.

SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome.

Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigate how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN downstream of NMDA receptor or metabotropic glutamate receptor (mGluR) stimulation. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1-/y mice, the unstimulated protein interaction network state resembled that of wildtype littermates stimulated with mGluR agonists, demonstrating resting state pre-activation of mGluR signaling networks. In contrast, interactions downstream of NMDAR stimulation were similar to WT. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated in FMR1-/y animals. We tested whether targeting SFKs in FMR1-/y mice could modify disease phenotypes, and found that Saracatinib (SCB), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1-/y mice. However, SCB treatment did not normalize the PIN to a wild-type-like state in vitro or in vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.

The ability to sense the environment is heterogeneously distributed in cell populations.

Channel capacity of signaling networks quantifies their fidelity in sensing extracellular inputs. Low estimates of channel capacities for several mammalian signaling networks suggest that cells can barely detect the presence/absence of environmental signals. However, given the extensive heterogeneity and temporal stability of cell state variables, we hypothesize that the sensing ability itself may depend on the state of the cells. In this work, we present an information-theoretic framework to quantify the distribution of sensing abilities from single-cell data. Using data on two mammalian pathways, we show that sensing abilities are widely distributed in the population and most cells achieve better resolution of inputs compared to an 'average cell'. We verify these predictions using live-cell imaging data on the IGFR/FoxO pathway. Importantly, we identify cell state variables that correlate with cells' sensing abilities. This information-theoretic framework will significantly improve our understanding of how cells sense in their environment.

Cell migration in dense microenvironments.

The nucleus has been viewed as a passenger during cell migration that functions merely to protect the genome. However, increasing evidence shows that the nucleus is an active organelle, constantly sensing the surrounding environment and translating extracellular mechanical inputs into intracellular signaling. The nuclear envelope has a large membrane reservoir which serves as a buffer for mechanical inputs as it unfolds without increasing its tension. In contrast, when cells cope with mechanical strain, such as migration through solid tumors or dense interstitial spaces, the nuclear envelope folds stretch, increasing nuclear envelope tension and sometimes causing rupture. Different degrees of nuclear envelope tension regulate cellular behaviors and functions, especially in cells that move and grow within dense matrices. The crosstalk between extracellular mechanical inputs and the cell nucleus is a critical component in the modulation of cell function of cells that navigate within packed microenvironments. Moreover, there is a link between regimes of nuclear envelope unfolding and different cellular behaviors, from orchestrated signaling cascades to cellular perturbations and damage.

Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness

Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.

The emerging promise of tumour mechanobiology in cancer treatment

Tumour cell biomechanics has lately came to the fore as a disparate feature that fosters cancer development and progression. Tumour mechanosensing entails a mechanical interplay amongst tumour cells, extracellular matrix (ECM) and cells of the tumour microenvironment (TME). Sensory receptors (mechanoceptors) detect changes of extracellular mechanical inputs such as various types of mechanical forces/stress and trigger oncogenic signalling pathways advocating for cancer initiation, growth, survival, angiogenesis, invasion, metastasis, and immune evasion. Moreover, alterations in ECM stiffness and potentiation of mechanostimulated transcriptional regulatory molecules (transcription factors/cofactors) have been shown to strongly correlate with resistance to anticancer drugs. On this basis, new mechanosensitive proteins emerge as potential therapeutic targets and/or biomarkers in cancer. Accordingly, tumour mechanobiology arises as a promising field that can potentially provide novel combinatorial regimens to reverse drug resistance, as well as offer unprecedented targeting approaches that may help to more effectively treat a large proportion of solid tumours and their complications.Here, we highlight recent findings regarding various aspects of tumour mechanobiology in the clinical setting and discuss evidence-based perspectives of developing diagnostic/prognostic tools and therapeutic approaches that exploit tumour−TME physical associations.

An automated method to discover true events and classification of intracellular Ca2+ profiles for endothelium in situ injury assay.

Introduction: Endothelial cells (ECs), being located at the interface between flowing blood and vessel wall, maintain cardiovascular homeostasis by virtue of their ability to integrate chemical and physical cues through a spatio-temporally coordinated increase in their intracellular Ca2+ concentration ([Ca2+]i). Endothelial heterogeneity suggests the existence of spatially distributed functional clusters of ECs that display different patterns of intracellular Ca2+ response to extracellular inputs. Characterizing the overall Ca2+ activity of the endothelial monolayer in situ requires the meticulous analysis of hundreds of ECs. This complex analysis consists in detecting and quantifying the true Ca2+ events associated to extracellular stimulation and classifying their intracellular Ca2+ profiles (ICPs). The injury assay technique allows exploring the Ca2+-dependent molecular mechanisms involved in angiogenesis and endothelial regeneration. However, there are true Ca2+ events of nearly undetectable magnitude that are almost comparable with inherent instrumental noise. Moreover, undesirable artifacts added to the signal by mechanical injury stimulation complicate the analysis of intracellular Ca2+ activity. In general, the study of ICPs lacks uniform criteria and reliable approaches for assessing these highly heterogeneous spatial and temporal events. Methods: Herein, we present an approach to classify ICPs that consists in three stages: 1) identification of Ca2+ candidate events through thresholding of a feature termed left-prominence; 2) identification of non-true events, known as artifacts; and 3) ICP classification based upon event temporal location. Results: The performance assessment of true-events identification showed competitive sensitivity = [0.9995, 0.9831], specificity = [0.9946, 0.7818] and accuracy = [0.9978, 0.9579] improvements of 2x and 14x, respectively, compared with other methods. The ICP classifier enhanced by artifact detection showed 0.9252 average accuracy with the ground-truth sets provided for validation. Discussion: Results indicate that our approach ensures sturdiness to experimental protocol maneuvers, besides it is effective, simple, and configurable for different studies that use unidimensional time dependent signals as data. Furthermore, our approach would also be effective to analyze the ICPs generated by other cell types, other dyes, chemical stimulation or even signals recorded at higher frequency.

New Insights into the Regulation of mTOR Signaling via Ca2+-Binding Proteins.

Environmental factors are important regulators of cell growth and proliferation. Mechanistic target of rapamycin (mTOR) is a central kinase that maintains cellular homeostasis in response to a variety of extracellular and intracellular inputs. Dysregulation of mTOR signaling is associated with many diseases, including diabetes and cancer. Calcium ion (Ca2+) is important as a second messenger in various biological processes, and its intracellular concentration is tightly regulated. Although the involvement of Ca2+ mobilization in mTOR signaling has been reported, the detailed molecular mechanisms by which mTOR signaling is regulated are not fully understood. The link between Ca2+ homeostasis and mTOR activation in pathological hypertrophy has heightened the importance in understanding Ca2+-regulated mTOR signaling as a key mechanism of mTOR regulation. In this review, we introduce recent findings on the molecular mechanisms of regulation of mTOR signaling by Ca2+-binding proteins, particularly calmodulin (CaM).

PIEZO1 activates non-canonical EGFR internalization and signaling.

EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. Both the soluble extracellular ligand, EGF, and mechanical inputs like matrix stiffness, cell adhesion, or stretch can activate EGFR-ERK signaling. However, the molecules transducing mechanical forces into EGFR signaling remain unidentified. We previously found that stretch promotes mitosis by mechanically activating the ion channel Piezo1 to trigger ERK signaling. Here, we show that Piezo1 provides the missing link to mechanical EGFR-ERK activation. Both EGF or the synthetic Piezo1 agonist Yoda1 triggered EGFR internalization and ERK activation, established markers of EGFR signaling. However, while EGF stimulation requires canonical EGFR tyrosine autophosphorylation, activation by Piezo1 requires non-canonical serine EGFR phosphorylation by a Src-p38 kinase axis. Additionally, Yoda1 stimulation of Piezo1 promoted cell cycle re-entry and proliferation via long-term nuclear accumulation of ERK, AP-1 (FOS and JUN), and YAP, typical of regenerative and malignant signaling. Our results suggest two modes of EGFR signaling: basal EGF-dependent signaling, requiring tyrosine autophosphorylation, and mechanically activated EGFR signaling, that results in sustained proliferation, critical to repair and regeneration, and cancer growth.

Mechanistic Target of Rapamycin Complex 1: From a Nutrient Sensor to a Key Regulator of Metabolism and Health

Mechanistic target of rapamycin complex 1 (mTORC1) is a multi-protein complex widely found in eukaryotes. It serves as a central signaling node to coordinate cell growth and metabolism by sensing diverse extracellular and intracellular inputs, including amino acid-, growth factor-, glucose-, and nucleotide-related signals. It is well documented that mTORC1 is recruited to the lysosomal surface, where it is activated and, accordingly, modulates downstream effectors involved in regulating protein, lipid, and glucose metabolism. mTORC1 is thus the central node for coordinating the storage and mobilization of nutrients and energy across various tissues. However, emerging evidence indicated that the overactivation of mTORC1 induced by nutritional disorders leads to the occurrence of a variety of metabolic diseases, including obesity and type 2 diabetes, as well as cancer, neurodegenerative disorders, and aging. That the mTORC1 pathway plays a crucial role in regulating the occurrence of metabolic diseases renders it a prime target for the development of effective therapeutic strategies. Here, we focus on recent advances in our understanding of the regulatory mechanisms underlying how mTORC1 integrates metabolic inputs as well as the role of mTORC1 in the regulation of nutritional and metabolic diseases.

Orthogonal Activation of Metabotropic Glutamate Receptor Using Coordination Chemogenetics.

Cell-surface receptors play a pivotal role as transducers of extracellular input. Although different cell types express the same receptor, the physiological roles of the receptor are highly dependent on cell type. To understand each role, tactics for cell-specific activation of the target receptor are in high demand. Herein, we developed an orthogonal activation method targeting metabotropic glutamate receptor 1 (mGlu1), a G-protein coupled receptor. In this method, direct activation via coordination-based chemogenetics (dA-CBC) was adopted, where activation of mGlu1 was artificially induced by a protein conformational change in response to the coordination of a metal ion or metal-ion complex. Our structure-based protein design and screening approach identified mGlu1 mutants that were directly activated by the coordination of Cu2+ or Zn2+, in addition to our previous Pd-complex-sensitive mGlu1 mutant. Notably, the activation of the mutants was mutually orthogonal, resulting in cell-type selective activation in a model system using HEK293 cells.

Mechanisms of How Random Input Controls Bursting Gene Expression

The process of gene expression is affected by many extracellular stimulus signals, and the stochasticity of these signals reshapes gene expression. To adapt the fluctuation of the extracellular environment, genes have many strategies for augmenting their survival probability, frequency modulation, and amplitude modulation. However, it is unclear how genes utilize the stochasticity of signals to regulate gene expression and which strategy will be chosen to maximize cellular function. Here, we analyze a simple mechanistic model to clarify the effect of extracellular random input on gene expression and burst kinetics at different timescales. We can see that in different contexts, extracellular noise has different effects on downstream gene expression, effects which include the following: (1) extracellular noise will make the ON‐OFF‐state dwell time drift, which will influence the burst frequency and burst size of downstream gene expression under different modulation paradigms; (2) comparing the burst parameter or gene expression products under different modulation paradigms, we can see that the amplitude signal is more sensitive in the case of extracellular noise input, whereas the signal in noiseless conditions is more sensitive when the random input is a fast process, which indicates that the amplitude signal is a superior and common signal in gene expression; and (3) extracellular random input will change the bimodality for gene expression, but its influence is different for gene expression products under different modulation paradigms. These qualitative results reveal that extracellular random input can prompt the gene to achieve its function quickly under different modulation paradigms.

See Spots? Look Deeper!

See Spots? Look Deeper!

MYH9 facilitates autoregulation of adipose tissue depot development.

White adipose tissue not only serves as a reservoir for energy storage but also secretes a variety of hormonal signals and modulates systemic metabolism. A substantial amount of adipose tissue develops in early postnatal life, providing exceptional access to the formation of this important tissue. Although a number of factors have been identified that can modulate the differentiation of progenitor cells into mature adipocytes in cell-autonomous assays, it remains unclear which are connected to physiological extracellular inputs and are most relevant to tissue formation in vivo. Here, we elucidate that mature adipocytes themselves signal to adipose depot–resident progenitor cells to direct depot formation in early postnatal life and gate adipogenesis when the tissue matures. Our studies revealed that as the adipose depot matures, a signal generated in mature adipocytes is produced, converges on progenitor cells to regulate the cytoskeletal protein MYH9, and attenuates the rate of adipogenesis in vivo.

The AMBRA1 E3 ligase adaptor regulates the stability of cyclinD.

The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclinD) couple these inputs to the initiation of DNA replication1. Increased levels of cyclinD promote cell division by activating cyclin-dependent kinases4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclinD-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer2,3. However, the mechanisms that regulate levels of cyclinD are incompletely understood4,5. Here we show that autophagy and beclin1 regulator1 (AMBRA1) is the main regulator of the degradation of cyclinD. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclinD in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclinD as a substrate receptor for the cullin4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclinD, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.

Cutting the Brakes on Ras-Cytoplasmic GAPs as Targets of Inactivation in Cancer.

Simple SummaryGTPase-Activating Proteins (RasGAPs) are a group of structurally related proteins with a fundamental role in controlling the activity of Ras in normal and cancer cells. In particular, loss of function of RasGAPs may contribute to aberrant Ras activation in cancer. Here we review the multiple molecular mechanisms and factors that are involved in downregulating RasGAPs expression and functions in cancer. Additionally, we discuss how extracellular stimuli from the tumor microenvironment can control RasGAPs expression and activity in cancer cells and stromal cells, indirectly affecting Ras activation, with implications for cancer development and progression.The Ras pathway is frequently deregulated in cancer, actively contributing to tumor development and progression. Oncogenic activation of the Ras pathway is commonly due to point mutation of one of the three Ras genes, which occurs in almost one third of human cancers. In the absence of Ras mutation, the pathway is frequently activated by alternative means, including the loss of function of Ras inhibitors. Among Ras inhibitors, the GTPase-Activating Proteins (RasGAPs) are major players, given their ability to modulate multiple cancer-related pathways. In fact, most RasGAPs also have a multi-domain structure that allows them to act as scaffold or adaptor proteins, affecting additional oncogenic cascades. In cancer cells, various mechanisms can cause the loss of function of Ras inhibitors; here, we review the available evidence of RasGAP inactivation in cancer, with a specific focus on the mechanisms. We also consider extracellular inputs that can affect RasGAP levels and functions, implicating that specific conditions in the tumor microenvironment can foster or counteract Ras signaling through negative or positive modulation of RasGAPs. A better understanding of these conditions might have relevant clinical repercussions, since treatments to restore or enhance the function of RasGAPs in cancer would help circumvent the intrinsic difficulty of directly targeting the Ras protein.

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae.

The human pathogen Vibrio cholerae is the causative agent of severe diarrheal disease known as cholera. Of the more than 200 “O” serogroups of this pathogen, O1 and O139 cause cholera outbreaks and epidemics. The rest of the serogroups, collectively known as non-O1/non-O139 cause sporadic moderate or mild diarrhea and also systemic infections. Pathogenic V. cholerae circulates between nutrient-rich human gut and nutrient-deprived aquatic environment. As an autochthonous bacterium in the environment and as a human pathogen, V. cholerae maintains its survival and proliferation in these two niches. Growth in the gastrointestinal tract involves expression of several genes that provide bacterial resistance against host factors. An intricate regulatory program involving extracellular signaling inputs is also controlling this function. On the other hand, the ability to store carbon as glycogen facilitates bacterial fitness in the aquatic environment. To initiate the infection, V. cholerae must colonize the small intestine after successfully passing through the acid barrier in the stomach and survive in the presence of bile and antimicrobial peptides in the intestinal lumen and mucus, respectively. In V. cholerae, virulence is a multilocus phenomenon with a large functionally associated network. More than 200 proteins have been identified that are functionally linked to the virulence-associated genes of the pathogen. Several of these genes have a role to play in virulence and/or in functions that have importance in the human host or the environment. A total of 524 genes are differentially expressed in classical and El Tor strains, the two biotypes of V. cholerae serogroup O1. Within the host, many immune and biological factors are able to induce genes that are responsible for survival, colonization, and virulence. The innate host immune response to V. cholerae infection includes activation of several immune protein complexes, receptor-mediated signaling pathways, and other bactericidal proteins. This article presents an overview of regulation of important virulence factors in V. cholerae and host response in the context of pathogenesis.

SAT-585 Autoregulation of Adipose Tissue Development

White adipose tissue not only serves as a reservoir for energy storage but also secretes a variety of hormonal signals and modulates systemic metabolism. A substantial amount of adipose tissue develops in early postnatal life, providing unique access to the formation of this important tissue. However, while a number of factors have been identified that can modulate the differentiation of progenitor cells into mature adipocytes in cell autonomous assays, it remains unclear which are connected to physiological extracellular inputs and are most relevant to tissue formation in vivo. We elucidated that mature adipocytes themselves signal to adipose depot-resident progenitor cells to direct depot formation in early postnatal life and gate adipogenesis when the tissue matures. Our studies reveal that, as the adipose depot matures, a previously unrecognized signal is generated in mature adipocytes that converges on progenitor cells to regulate the cytoskeleton and attenuate the rate adipogenesis in vivo. This signal toggles the adipose depots from developmental to tissue homeostatic levels of adipogenesis.