Biology subjects

Nandakumar, S.

Publications and source records attributed to Nandakumar, S..

17 recordsLinked to original sources

bioRxiv2026

Basolateral amygdala dopamine signals behavioural salience across exploration and learning

Animals must balance exploration with threat avoidance, yet how neuromodulatory signals shape information-seeking states remains unclear. Using fibre photometry recordings in the basolateral amygdala in freely moving mice, we show that dopamine release is selectively elevated during self-initiated exploratory actions, adapts with repeated exposure, and tracks the behavioural relevance of predictive cues in associative learning and extinction. Our results advance current models of amygdala dopamine function by suggesting that it conveys a state-dependent salience signal that highlights behaviourally relevant moments arising from both environmental cues and self-generated exploration, thereby priming amygdala circuits for plasticity.

neuroscience↗

bioRxiv2026

SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is clinically and molecularly defined by oncogenic driver mutations, identification of which has led to the development of driver-targeted therapies and substantial improvements in prognosis for subsets of LUAD patients. Recent studies assessing clinical outcomes in the context of multigenic alterations have identified secondary mutations that might explain differential responses to targeted therapies, chemotherapies and immunotherapies. Genetic inactivation or loss of SMARCA4, which frequently co-occurs with loss-of-function mutations in STK11 and KEAP1, is especially predictive of poor prognosis and shorter overall survival in LUAD patients, regardless of driver status. We sought to examine the clinical and functional associations of SMARCA4 deficiency in LUAD, with or without co-associated STK11/KEAP1 loss-of-function. MethodsWe examined correlation between SMARCA4 loss, gene expression and prognosis through genomic and transcriptomic profiling of clinically annotated LUAD samples. We generated isogenic cell line models with genetic knockouts of SMARCA4 with or without concomitant STK11 and KEAP1 to profile mutationally-defined genotypes of interest in vitro and in vivo. Lastly, we interrogated the functional dependency of SMARCA4/STK11/KEAP1 triple mutant models on TGF-{beta} signaling to assess its potential as a therapeutic target. ResultsSMARCA4/STK11/KEAP1 triple mutant LUAD is associated with poor survival and high frequency of multisite metastasis. SMARCA4/STK11/KEAP1 triple knockout models showed enhanced migration and invasion in vitro, and diversified organotropism in an in vivo intracardiac xenograft metastasis assay. RNA-Seq and DNaseI-Seq of these in vitro models and clinical samples identified upregulation of TGF-{beta} signaling and EMT gene expression signatures, and corresponding changes in chromatin accessibility, in SMARCA4/STK11/KEAP1 triple mutant LUAD. ConclusionsWe identify SMARCA4/STK11/KEAP1 triple mutant LUAD as a prognostically significant disease subset and nominate TGF-{beta} signaling as a potential therapeutic target.

cancer biology↗

bioRxiv2026

MYC pathway reprogramming through a TIP60 coactivator switch in neuroendocrine lineage transition in prostate cancer

Prostate adenocarcinomas (PRAD) can acquire resistance to androgen receptor signaling inhibitors through lineage transition to a cell state known as neuroendocrine prostate cancer (NEPC). Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth/survival by recruitment of the TIP60/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.

cancer biology↗

bioRxiv2026

Dependencies in heterogeneous, lineage plastic patient-derived prostate cancer organoids revealed through integrated single-cell multiomics and CRISPR screening

Lineage plasticity and tumor heterogeneity limit the effectiveness of targeted therapies, yet the functional dependencies used to nominate therapeutic targets are often derived from homogeneous systems that fail to capture this complexity. Here, we establish a framework to resolve state-specific genetic vulnerabilities by integrating single-cell multiomics (RNA and ATAC) with pooled CRISPR-Cas9 screening across a large panel of patient-derived organoids (PDOs) from castrate-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). We generate a single-cell multiome atlas spanning >190,000 cells across 22 PDOs, defining seven lineage states--including intermediate and plastic populations not resolved by bulk profiling--and demonstrate that these lineage programs robustly classify independent transcriptomic datasets from prostate cancer patient tumors. By systematically coupling this atlas to subtype-resolved CRISPR screens, we construct a functional dependency map linking cell state in heterogeneous 3D human tumor models. We show that intratumoral heterogeneity fundamentally reshapes the interpretation of gene essentiality, whereby gene-level depletion reflects the composite behavior of co-existing subpopulations, and identify a general principle in which resistant "limiting" populations disproportionately determine aggregate fitness effects. This framework reveals both canonical and previously unrecognized lineage-restricted dependencies within highly plastic tumor and NEPC states, including a therapeutically targetable dependency on the aryl hydrocarbon receptor (AHR) in a novel hybrid stem-like/ASCL1 population. Together, these data establish an extensive multi-dimensional prostate cancer resource, identify novel lineage-resolved biology, and provide a generalizable strategy for interpreting functional genomics in heterogeneous human tumors.

cancer biology↗

bioRxiv2026

Single Cell Transcriptomics and Surface Protein Expression Reveal Distinct Cellular and Molecular Phenotypes in Human RPESC-RPE and PSC-RPE

Current retinal pigment epithelium (RPE) cell replacement strategies in trials for age-related macular degeneration (AMD) are based on either pluripotent stem cell (PSC) or adult RPE stem cell (RPESC) sources. We used Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) to simultaneously assess single-cell transcriptomic and surface protein information, comparing these two RPE sources. Both RPESC-RPE and PSC-RPE expressed key RPE markers and exhibited cellular heterogeneity. However, RPESC-RPE had higher expression of genes related to mature retinal functions, whereas PSC-RPE had greater expression of genes involved in stem cell development and differentiation. We identified two surface proteins that distinguished the cell types. The "dont eat me" signal, CD24, was detected robustly on adult RPESC-RPE cells, while CD57 was detected on most PSC-RPE cells. The differences in gene and surface protein expression suggest that the two RPE sources differ in functional, adhesion, and immunomodulatory properties, which may impact transplantation outcomes.

cell biology↗

bioRxiv2026

Systematic functional dissection of germline noncoding risk variants impacting clonal hematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor condition characterized by the expansion of blood cell clones harboring somatic mutations originating in hematopoietic stem cells (HSCs). Since individuals with CHIP face a high risk of developing myeloid malignancies, targeting CHIP clones could provide a viable strategy for leukemia prevention. Despite its clinical significance, the mechanisms underlying CHIP predisposition and progression remain poorly understood. Recent genome wide association studies (GWAS) have identified several non-coding genetic loci that are strongly associated with CHIP; however, their underlying mechanisms still remain unknown. We hypothesize that risk variants in these non-coding loci modulate enhancer elements active in HSCs. To test this, we selected 1,374 non-coding variants from 51 loci associated for CHIP risk in the UK Biobank and screened them for regulatory activity using a Massively Parallel Reporter Assay (MPRA). We performed our lentiviral MPRA screen in MUTZ-3 cells, a human hematopoietic cell line relevant to HSCs, which express CD34 surface marker and are dependent on HSC-specific transcription factors. Using a MPRA library of [~]73,000 constructs in CD34+ fraction of MUTZ-3 cells, we identified 87 variants representing 32 GWAS loci. We used targeted genome editing to demonstrate endogenous enhancer activity across 3 MPRA variants that affect the transcription of NKD2, FLT3, and MSI2. Our functional studies on MSI2 indicate that presence of higher levels of MSI2 mediated by CHIP risk allele enhances the clonal expansion of TET2 knockout hematopoietic stem and progenitor cells, providing a mechanistic link whereby non-coding genetic variants can influence the expansion of mutant CHIP clones.

genetics↗

bioRxiv2025

Extracellular matrix regulates lineage plasticity in prostate cancer through YAP/TEAD

Treatment-related neuroendocrine prostate cancer (NEPC) is an increasingly frequent mechanism of resistance to androgen receptor pathway inhibitor (ARPI) therapy in prostate adenocarcinoma (PRAD). This lineage transition is dependent on upregulation of the NE-specifying transcription factor ASCL1, typically in a genetic background of RB1 and TP53 loss. Here we identify extracellular matrix-integrin-YAP1/TEAD signaling as a critical brake on NEPC lineage transition. Deletion of Itgb1, the shared B1 subunit required for collagen and laminin-mediated integrin activation, is sufficient to induce ASCL1 and NE lineage gene expression, by activating LATS1/2 kinases with subsequent inactivation of YAP1/TEAD signaling. Conversely, restoration of YAP1/TEAD signaling by pharmacological LATS1/2 inhibition, or by expression of constitutively active YAP1/TAZ mutants, prevents or reverts NEPC lineage transition. NOTCH and AR cooperate with YAP/TEAD to repress ASCL1, such that combined inhibition leads to complete reprograming of PRAD into NEPC in vitro, providing a dynamic platform to dissect the molecular events responsible for lineage transition over time. We find that lineage transition is accompanied by a redistribution of FOXA1 and TEAD cistromes from PRAD to NEPC-specific enhancers and requires the pioneering activity of FOXA1. Thus, extracellular matrix/integrin signaling in the PRAD tumor microenvironment restrains NE lineage plasticity, highlighting a potential path for pharmacological inhibitors in modulating treatment-induced lineage change.

cancer biology↗

bioRxiv2025

Kinesin-induced buckling reveals the limits of microtubule self-repair

Microtubules are stiff cytoskeletal polymers whose ability to rapidly switch between growth and disassembly relies on a metastable lattice. This metastability is also reflected in their sensitivity to environmental conditions and in intrinsic lattice dynamics, where spontaneous tubulin loss is balanced by tubulin incorporation from solution - a process that also enables microtubules to self-repair when damaged. Whether such intrinsic self-repair is sufficient to preserve microtubule integrity during dynamic molecular-motor induced buckling, which frequently occurs in cells, remains unclear. Here, we show that kinesin-driven microtubule buckling in vitro induces severe lattice damage, leading to extensive tubulin incorporation. In many cases, however, the damage exceeds the microtubules capacity for self-repair, resulting in breakage. In contrast, microtubules survive continuous buckling substantially longer in the presence of intracellular factors. Our results identify the limits of intrinsic microtubule self-repair and demonstrate that additional cellular mechanisms are essential to maintain microtubule integrity under sustained mechanical load.

biophysics↗

bioRxiv2025

Ring canals in the larval adipose of Drosophila buffer stress response

Cells in metabolically active tissues with high biosynthetic and secretory demands often use robust stress-responsive mechanisms to maintain endoplasmic reticulum (ER) homeostasis. Coordinating such robust stress response mechanisms requires intercellular communication and coordination. Such modalities of intercellular communication have been relatively understudied in the context of stress tolerance. Here, we use the Drosophila melanogaster third instar fat body to demonstrate that adipocytes communicate with each other through intercellular bridges called ring canals to buffer endoplasmic reticulum stress. The fat body supports the exponential growth from embryo to late larval stage over a short period of time through its energy storage and secretory functions, enduring a high basal level of ER stress in the process. We discovered that individual cells in the fat body are paired to one neighboring cell through ring canals. We further demonstrate that ring canals mediate rapid and highly specific intercellular cargo and organellar trafficking, and allow the transport of cytoplasmic, ER-bound and Golgi vesicular proteins. Disrupting fat body ring canals resulted in higher levels of ER stress response markers, aberrant cell size, as well as increased cell lethality in response to exogenous stress. We also find that animals with disrupted fat body ring canals display an overall delay in larval development, likely due to reduced secretion of larval serum proteins from the fat body. In sum, our work reveals a novel feature of intercellular communication in adipose tissue that serves to buffer ER stress across cells which is required for both homeostatic secretory function and maintaining tissue viability under exogenous stress.

cell biology↗

bioRxiv2025

BRCA2 reversion mutation-independent resistance to PARP inhibition in prostate cancer through loss of function perturbations in the DNA pre-replication complex

Recent approvals of PARP inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer (mCRPC) necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in [~]50-80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only [~]50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2{Delta}/{Delta} prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent sgRNAs targeting three different members (Cdt1, Cdc6, Dbf4) of the DNA pre-replication complex (pre-RC), each of which independently conferred resistance to olaparib and the next generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2{Delta}/{Delta}, Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, [~]50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1. Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition in BRCA-mutant cancers. SignificanceHere, we address a major limitation in the effectiveness of PARP inhibitors in BRCA-mutant prostate cancer treatment: only [~]50% of patients respond despite clear genomic evidence of defective homologous recombination. Prior efforts to study PARP inhibitor resistance in prostate cancer have been plagued by the lack of suitable cell lines. We overcame this challenge using primary prostate organoids coupled with genome-wide CRISPR screening. The key finding is that loss of function mutations in the DNA pre-replication complex confer PARP inhibitor resistance. These genes map to chromosomal regions frequently lost in prostate cancer and could therefore serve as potential biomarkers of treatment response. Pharmacologic inhibition of geminin, a negative regulator of the pre-replication complex, can restore PARP inhibitor sensitivity.

cancer biology↗

bioRxiv2025

The mechanism how Pretubulysin-induced microtubule disassembly improves T cell search efficiency

To clean tissue from tumorigenic and infected cells, cytotoxic T lymphocytes (CTLs) must navigate confined environments in vivo, locate the infected cells and eliminate them. Impaired CTL migration towards the tumor can limit the efficacy of immunotherapy. Microtubules (MTs) have emerged as promising targets, because destabilizing MTs enhances T-cell migration and subsequent killing, yet the underlying mechanisms are poorly understood. Here, we use pretubulysin, a potent MT depolymerizer, to uncover how MT dynamics regulate CTL motility. Complete MT disassembly markedly increased CTL infiltration and migration in 3D matrices. To investigate how altered migration affects target elimination, we employed a persistent random-walk model parameterized solely with experimental motility data. The model shows that the increase in speed and persistence induced by pretubulysin explains enhanced search efficiency increasing the encounter rate of CTLs with target cells. The simulations also predict how these gains in search efficiency scale with tissue thickness and CTL density. Mechanistically, MT depolymerization in activated CTLs triggers localized actomyosin accumulation at the uropod. This enhances rear contraction forces and promotes faster, more persistent migration and efficient search. Our findings clarify how MT dynamics influence CTL ability to eliminate targets in 3D environments and highlights the potential of MT-targeting agents such as pretubulysin to optimize T cell-based immunotherapies.

cell biology↗

bioRxiv2024

Sharing Data from the Human Tumor Atlas Network through Standards, Infrastructure, and Community Engagement

The Data Coordinating Center (DCC) of the Human Tumor Atlas Network (HTAN) has played a crucial role in enabling the broad sharing and effective utilization of HTAN data within the scienti[fi]c community. Data from the [fi]rst phase of HTAN are now available publicly. We describe the diverse datasets and modalities shared, multiple access routes to HTAN assay data and metadata, data standards, technical infrastructure and governance approaches, as well as our approach to sustained community engagement. HTAN data can be accessed via the HTAN Portal, explored in visualization tools--including CellxGene, Minerva, and cBioPortal--and analyzed in the cloud through the NCI Cancer Research Data Commons nodes. We have developed a streamlined infrastructure to ingest and disseminate data by leveraging the Synapse platform. Taken together, the HTAN DCCs approach demonstrates a successful model for coordinating, standardizing, and disseminating complex cancer research data via multiple resources in the cancer data ecosystem, offering valuable insights for similar consortia, and researchers looking to leverage HTAN data.

cancer biology↗

bioRxiv2021

Skin specimen as an alternative to brain tissue for post mortem rabies diagnosis in animals to scale up animal rabies surveillance

BackgroundDetection of the virus or some of its specific components using WHO and OIE recommended standard laboratory tests is the only way to get a reliable diagnosis of rabies. Brain tissue is the preferred specimen for post-mortem diagnosis of rabies in both humans and animals. Higher biosecurity requirements, skill and transportation facilities required for collection and transport of brain or whole carcass to the laboratory is one of the reasons for the poor rabies surveillance in animals. Point of care testing with simple, reliable and easy to operate devices would be an ideal approach for providing rapid results. MethodsThe study evaluated diagnostic performance of two reference tests, DFAT and RTPCR on skin specimen, to assess its suitability as an alternative of brain tissue for post mortem rabies diagnosis in animals. Brain tissue and skin sample belonging to different species of animals (n=90) collected at necropsy were compared using Fluorescent Antibody Test and RT PCR, internationally approved methods for rabies diagnosis. ResultsValidation of RT-PCR on skin and DFAT on skin in comparison with DFAT on brain as gold standard gave a sensitivity of 98% (95% CI:94.1-100) and 80% (95% CI:71.8-88.2) respectively. Specificity was 100% in both tests. ConclusionThe findings highlight the potential of skin specimen for improving rabies surveillance in animals especially in resource poor countries. Author SummaryThe present study was undertaken to define a reliable protocol for diagnosing animal rabies using skin specimen, a superficial tissue sample which is collected in a non-invasive manner for post-mortem diagnosis. Our aim was to design a protocol to replace the classical post-mortem diagnostic method that uses brain biopsy with an ultimate target of stepping up rabies surveillance in animals. Brain tissue and skin sample belonging to different species of animals collected at necropsy were compared using Fluorescent Antibody Test and RT PCR, internationally approved methods for rabies diagnosis. The study established that RT PCR on skin specimen is rapid, sensitive and specific, opening its potential as an ideal rabies surveillance tool overcoming the logistical challenges of carcass transportation to reference laboratories and alleviating biosafety concerns associated with brain collection. The study highlights the potential of skin specimen for improving rabies surveillance in animals especially in resource poor countries.

microbiology↗

bioRxiv2021

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling

Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. We further unravel a network of stress responses upregulated in BRCA-mutated tumors. Using cancer organoids and cell co-cultures, we show that the transcriptional shift of pancreatic stellate cells into CLU+ CAFs is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research. SignificanceBRCA1/2 mutations initiate some of the deadliest cancers, yet the fibroblastic microenvironment of BRCA-mutated cancers remains uncharted. Our work addresses a major unsolved question - to what extent is the tumor microenvironment determined by cancer mutations? We find that BRCA mutations in the cancer cells affect the composition of CAFs in PDAC. These findings have direct implications for diagnosis and for efforts to exploit CAFs for therapy.

cancer biology↗

bioRxiv2021

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

cancer biology↗

bioRxiv2019

Polyploidy in the adult Drosophila brain

Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animals lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageing Drosophila melanogaster brains.

developmental biology↗

bioRxiv2019

Endocycling in the adult Drosophila accessory gland

The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate containing two secretory epithelial cell types, termed main and secondary cells. This tissue is responsible for making and secreting seminal fluid proteins and other molecules that contribute to successful reproduction. The cells of this tissue are bi-nucleate and polyploid, due to variant cell cycles that include endomitosis and endocycling during metamorphosis. Here we provide evidence of additional cell cycle variants in this tissue. We show that main cells of the gland are connected by ring canals that form after the penultimate mitosis and we describe an additional post-eclosion endocycle required for gland maturation that is dependent on juvenile hormone signaling. We present evidence that the main cells of the Drosophila melanogaster accessory gland undergo a unique cell cycle reprogramming throughout organ development that results in step-wise cell cycle truncations culminating in cells containing two octoploid nuclei with under-replicated heterochromatin in the mature gland. We propose this tissue as a model to study developmental and hormonal temporal control of cell cycle variants in terminally differentiating tissues.

developmental biology↗