Biology subjects

Na, J.

Publications and source records attributed to Na, J..

At least 19 recordsLinked to original sources

bioRxiv2026

TGF-β signalling regulates the balance between protective and regulatory CD4+ T cell responses in visceral leishmaniasis

Visceral leishmaniasis (VL) is a potentially fatal parasitic disease in which effective immunity requires sufficient inflammation to control parasites while limiting immune-mediated tissue damage. Transforming growth factor-beta (TGF{beta}) is an important regulator of immune homeostasis and has been implicated in VL, but how it directly controls parasite-specific CD4 T cell responses remains poorly understood. We used complementary transgenic mouse models with either enhanced or ablated TGF{beta} signalling in T cells during Leishmania donovani infection, combined with adoptive co-transfer of parasite-specific CD4 T cells to distinguish cell-intrinsic effects. Enhanced TGF{beta} signalling impaired hepatic parasite control and suppressed CD4 T cell immunity, reducing T helper 1 (Th1) cell differentiation, proliferation, accumulation of antigen-experienced cells, and expression of cytolytic molecules. Conversely, ablation of TGF{beta} signalling improved parasite control and promoted CD4 T cell expansion and Th1 cell differentiation, while increasing expression of cytolytic molecules and reducing interleukin-10-producing type 1 regulatory T (Tr1) cells. Adoptive co-transfer experiments confirmed that TGF{beta} directly restrained the expansion and Th1 cell differentiation of parasite-specific CD4 T cells and their acquisition of cytolytic features. Loss of signalling also impaired development of Tr1 cells and reduced expression of several chemokine receptors and co-inhibitory molecules associated with their regulatory function. However, enhanced signalling did not increase Tr1 cell development, indicating that the relationship between TGF{beta} signalling and immune regulation is not linear. TGF{beta} is a key cell-intrinsic regulator of CD4 T cell fate during experimental VL. Rather than acting solely as a general suppressor of inflammation, it calibrates the balance between protective and regulatory immunity by controlling CD4 T cell expansion, differentiation and effector function. Author summaryVisceral leishmaniasis (VL) is a potentially fatal disease caused by Leishmania parasites. The immune system must generate a strong enough response to control these parasites while preventing excessive inflammation that can damage tissues. We investigated how transforming growth factor-beta (TGF{beta}), an important regulator of immune responses, helps maintain this balance. Using mice in which signalling by TGF{beta} was either increased or removed specifically in T cells, we found that this pathway strongly influenced the development and function of CD4 T cells during infection. Increasing signalling suppressed the expansion of these cells and their development into inflammatory cells associated with parasite control. In contrast, removing signalling enhanced these responses and improved early parasite control, but also reduced the development of regulatory T cells that can limit inflammation. By studying parasite-specific T cells directly, we showed that many of these effects resulted from TGF{beta} acting within the T cells themselves. Our findings show that TGF{beta} does more than simply suppress immunity during VL. It helps determine the balance between CD4 T cell responses that control parasites and those that regulate inflammation, providing new insight into how immunity is shaped during chronic infection.

immunology↗

bioRxiv2026

Cryptic disease-prone states in human mesocortical assembloids revealed by multimodal profiling

Neurodegenerative diseases are characterized by synaptic failure, aberrant protein accumulation, and neuroglial dysfunction that emerge long before clinical onset. Although brain assembloids, which recapitulate interregional circuit connectivity beyond the scope of single organoids, significantly advance the modeling of circuit pathophysiology, they are predominantly evaluated through single-modality approaches that cannot resolve the functional and molecular heterogeneity underlying differential disease susceptibility. Here we show that morphologically identical human iPSC-derived dorso forebrain-midbrain mesocortical assembloids (MCAs) spontaneously bifurcate into disease-prone and non-prone states under identical culture conditions, revealing that MCA heterogeneity reflects intrinsic neurodegeneration susceptibility rather than stochastic culture variability. Using integrated electrophysiological, molecular, and spatial profiling, we find that disease-prone MCAs exhibit a temporally ordered molecular cascade in which neurofilament light chain elevation precedes tau dysregulation, mirroring the sequential biomarker trajectories observed in pre-symptomatic human neurodegeneration. Disease-prone MCAs further display selective cortical hyperexcitability and aberrant brainwave-like oscillatory dynamics that remain undetectable by any single modality. Spatially, a discrete junction-like neuronal population at the midbrain-forebrain interface shows transcriptional priming for synaptic overactivation alongside impaired astrocytic glutamate clearance, defining a spatially confined neuron-glial uncoupling as a candidate early origin of the disease-prone state. These findings reframe MCA heterogeneity as a biological window into pre-symptomatic neurodegeneration, with broad implications for disease modeling, risk stratification, and therapeutic discovery.

neuroscience↗

bioRxiv2025

Maternal effects regulate population genetic structure by altering intraspecific competitive relationships

O_LIThe transgenerational plasticity of maternal effects on offspring phenotypes has been well recognized, however, weather maternal effect can drive dynamic changes in population genetic structure by modifying the competitive dynamics among offspring is still unclear. C_LIO_LIAfter evaluation of the reliability of COI metabarcoding for intraspecific clone quantification using a monogonont rotifer Brachionus calyciflorus as the model animal, a high-frequency dynamic monitoring experimental system was set to measure maternal effect on temporal dynamics in gene frequencies within mixed populations containing morphologically identical clones. C_LIO_LIResults showed that maternal effects significantly enhanced the competitive fitness of the target offspring clone, leading to a rapid increase in its frequency inside the population. However, this advantage last for a few generations, and gradually diminished or even reversed as the maternal effects attenuated across generations. C_LIO_LITemperature dynamically affected the duration of maternal effect: higher temperature shortened the duration of maternal effects on population genetic dynamics, while lower temperature prolonged it. C_LIO_LIBy population dynamic monitoring, this study revealed the transient nature of maternal effect as a non-genetic buffering mechanism, providing an integrative theoretical framework for understanding the dynamic integration of short-term plasticity and long-term selection pressure in adaptive evolution of intraspecific clones. C_LI

ecology↗

bioRxiv2025

Mothers choice：maternal effects on the offspring population dynamics differed between exposure to microcystin-free algae Microcystis aeruginosa and chemical MC-LR environments in the rotifer Brachionus calyciflorus

Maternal effects can affect the offspring population dynamics by influence on the offsprings phenotypes related to fitness, which is of great significance in regulation of population dynamics. The inhibitory effect of bloom algae Microcystis aeruginosa on the rotifer Brachionus calyciflorus has been extensively studied. However, weather algae M. aeruginosa or its toxin MC-LR will affect rotifers population dynamic via maternal effect is not clear yet. In this study, we investigated if fitness related phenotypes would change in offspring from mothers experienced microcystin-free M. aeruginosa or MC-LR stress environments by population dynamic, life history traits, and morphology respectively. We find that the survival and reproduction of offspring decreased under maternal microcystin-free M. aeruginosa stress, but increased under maternal MC-LR stress. Our results indicate that the maternal effects act on the offspring in different forms when faced with different environments. Our research further demonstrates that, unlike the common belief that algal toxins are the main factor inhibiting rotifer population growth, non-toxic Microcystis aeruginosa in fact shows a more potent suppressive effect.

ecology↗

bioRxiv2025

Defining the roles of NKG7 expressed by CD4+ and CD8+ T cells during malaria

Malaria, caused by Plasmodium parasites, is a significant global health issue. CD4+ and CD8+ T cells are important for immunity against Plasmodium infections, but the specific roles of many immune-related effector molecules in T cells remain poorly defined. Here, we investigated the function of NK cell granule protein 7 (NKG7) in T cells during malaria, focusing on its role in CD4+ and CD8+ T cells in Plasmodium blood-stage responses. In a non-lethal malaria model, NKG7 played a protective role in CD4+ T cell responses, affecting pro-inflammatory T helper 1 (Th1), IL-10-producing type 1 regulatory (Tr1), and T follicular helper cell development. In a model of cerebral malaria, NKG7 was shown to have a cell-intrinsic role in CD4+ T cells for perforin and granzyme B expression, as well as the development of Tr1 cells. Human investigations involving peripheral blood mononuclear cells from volunteers participating in controlled human P. falciparum malaria infection studies, as well as endemic country patients with P. falciparum and P. vivax malaria, corroborated these findings. High NKG7 expression in T cells from Plasmodium-infected humans was observed, as well as differences in NKG7 expression based on the infecting Plasmodium species. NKG7 expression was associated with both cytotoxic and non-cytotoxic T cells, indicating varied functions following infection. These results advance our understanding about NKG7s role in T cell-mediated malaria immunity and suggest potential for targeting NKG7 to improve outcomes following Plasmodium infection.

immunology↗

bioRxiv2025

Tissue-specific improvements in CD4+ T cell responses after treatment for visceral leishmaniasis.

Visceral leishmaniasis (VL) is a life-threatening parasitic disease that requires robust CD4+ T cell-mediated immunity for parasite control. However, the heterogeneity and transcriptional dynamics of CD4+ T cell responses in VL remain poorly defined. In this study, we use a model of experimental VL with tissue-specific immunity and single-cell RNA sequencing to provide a high-resolution assessment of CD4+ T cell responses. Our analysis reveals the complexity of CD4+ T cell differentiation in VL, identifying distinct Th1 subsets with transcriptional heterogeneity that may reflect functional specialisation. Despite minimal transcriptional differences between splenic and hepatic CD4+ T cells, we identified shifts in subset composition, including the emergence of a stem-like CD4+ T cell population in the spleen, which was suppressed by the transcription factor Bhlhe40. Bhlhe40 deficiency skewed CD4+ T cell differentiation, impairing Th1 responses while promoting Tr1 cells, resulting in defective parasite control in the liver. Additionally, AmBisome treatment induced a profound transcriptional shift in CD4+ T cells, leading to the maintenance of stem-like CD4+ T cells in the spleen and the expansion of tissue resident memory-like cells in the liver. These findings uncover key regulatory mechanisms that shape CD4+ T cell differentiation in VL and provide insights into how immune-modulatory strategies could enhance long-term immunity.

immunology↗

bioRxiv2025

The N-terminal order-disorder transition is a critical determinant for a metamorphosis of IscU

IscU, a key scaffold protein mediating the biogenesis of iron-sulfur (Fe-S) clusters, exhibits metamorphic characteristics crucial for its versatile and efficient function. Previous studies have demonstrated that IscU has two interconverting conformations: the structured state (S-state) and the disordered state (D-state), each contributing to its distinct functionality and interaction network. Despite its physiological importance, the precise mechanism underpinning the maintenance of IscUs unique structural heterogeneity has remained elusive. In this study, we used computational and experimental approaches to reveal that the N-terminal order-disorder plays a critical role in the metamorphic modulation of IscU. We found that the N-terminal region displays greater structural plasticity, which is linked to other regions of IscU through coevolutionary relationships. Moreover, we demonstrated that the degree of orderliness in the N-terminal region correlates positively with the stabilization of IscUs S-state and negatively with its affinity for HscA. This indicates that the flexibility in the N-terminal region is finely tuned to optimize IscUs physiological efficiency and efficacy. Finally, our data suggest that a peptide mimicking the N-terminal motif can modulate IscUs metamorphic properties, suggesting a novel therapeutic potential for related pathogenic processes.

biochemistry↗

bioRxiv2024

Co-transcriptional RNA processing boosts zygotic gene activation

Transcription decodes protein-coding genes and interprets regulatory information embedded in the genome by generating RNA. In eukaryotes, gene transcription is coupled with RNA processing via the carboxyl terminal domain (CTD) of RNA polymerase (Pol) II, which enhances messenger RNA (mRNA) production. We propose that co-transcriptional RNA processing is essential for zygotic gene activation (ZGA), transitioning the transcription program from noncoding to protein-coding after fertilization. Truncating the CTD in mouse cells disrupts this coupling, halting global mRNA synthesis and increasing noncoding RNA (ncRNA) levels through enhanced intergenic transcription and RNA stabilization. CTD truncation also triggers epigenetic reprogramming and nuclear reorganization towards totipotency, resembling early cleavage embryos. Mechanistically, the CTD restrains nonproductive polymerase activity in noncoding sequences, while at protein-coding genes requiring RNA processing, it promotes elongation by facilitating polymerase promoter-proximal pausing, transcription directionality, and velocity. Longer CTD lengths enhance gene activity, likely evolving to accommodate the increasing noncoding sequences in mammalian genomes.

developmental biology↗

bioRxiv2023

Saturation genome editing-based functional evaluation and clinical classification of BRCA2 single nucleotide variants

Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing-based functional characterization of 97% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants that is encoded by exons 15 to 26. The assay was based on deep sequence analysis of surviving endogenously targeted haploid cells. A total of 7013 SNVs were characterized as functionally abnormal (n=955), intermediate/uncertain, or functionally normal (n=5224) based on 95% agreement with ClinVar known pathogenic and benign standards. Results were validated relative to batches of nonsense and synonymous variants and variants evaluated using a homology directed repair (HDR) functional assay. Breast cancer case-control association studies showed that pooled SNVs encoding functionally abnormal missense variants were associated with increased risk of breast cancer (odds ratio (OR) 3.89, 95%CI: 2.77-5.51). In addition, 86% of tumors associated with abnormal missense SNVs displayed loss of heterozygosity (LOH), whereas 26% of tumors with normal variants had LOH. The functional data were added to other sources of information in a ClinGen/ACMG/AMP-like model and 700 functionally abnormal SNVs, including 220 missense SNVs, were classified as pathogenic or likely pathogenic, while 4862 functionally normal SNVs, including 3084 missense SNVs, were classified as benign or likely benign. These classified variants can now be used for risk assessment and clinical care of variant carriers and the remaining functional scores can be used directly for clinical classification and interpretation of many additional variants. SummaryGermline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to several types of cancer. However, variants of uncertain significance (VUS) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants to facilitate current and future clinical management of individuals with these variants. Here we show the results from a saturation genome editing (SGE) and functional analysis of all possible single nucleotide variants (SNVs) from exons 15 to 26 that encode the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants. The assay was based on deep sequence analysis of surviving endogenously targeted human haploid HAP1 cells. The assay was calibrated relative to ClinVar known pathogenic and benign missense standards and 95% prevalence thresholds for functionally abnormal and normal variants were identified. Thresholds were validated based on nonsense and synonymous variants. SNVs encoding functionally abnormal missense variants were associated with increased risks of breast and ovarian cancer. The functional assay results were integrated into a ClinGen/ACMG/AMP-like model for clinical classification of the majority of BRCA2 SNVs as pathogenic/likely pathogenic or benign/likely benign. The classified variants can be used for improved clinical management of variant carriers.

genomics↗

bioRxiv2023

Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis

Besides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGF{beta} transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced cell migration and metastasis in mouse models. Furthermore, knockout of CtBP2 suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGF{beta} mRNA upregulation as well as cell invasion. Moreover, cleavage under targets and release using nuclease (CUT&RUN) coupled with next generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor region of genes encoding TGF{beta} and its signaling pathway in the cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1.

cancer biology↗

bioRxiv2023

Ambient temperature crystal structure of Escherichia coli CyaY protein displays alternate conformation

Frataxin is a 23 KDa mitochondrial iron-binding protein that is involved in biogenesis of iron sulfur clusters. A deficiency in frataxin leads to Friedreichs ataxia, a progressive neurodegenerative disorder. The bacterial ortholog of eukaryotic mitochondrial frataxin, CyaY, is thought to play a role in iron sulfur cluster assembly as an iron supplier, making it an important target for study. Here, we present the first ambient temperature crystal structure of CyaY protein from Escherichia coli, obtained using the Turkish Light Source "Turkish DeLight". This study reveals the dynamic structural characteristics of CyaY at near-physiological temperature and displays an alternate conformation, highlighting the importance of temperature considerations in protein structure characterization and providing new insights into the proteins flexibility.

biochemistry↗

bioRxiv2022

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

The development of highly effective malaria vaccines and improving drug treatment protocols to boost anti-parasitic immunity is critical for malaria elimination. However, these efforts are hampered by parasite-specific immunoregulatory networks that are rapidly established following exposure to malaria parasites. Here, we identify stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. STING activation by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription that promoted development of IL-10 and IFN{gamma} co-producing CD4+ T (type I regulatory; Tr1) cells. CD4+ T cell sensitivity to STING phosphorylation increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. Finally, we found the JAK1/2 inhibitor ruxolitinib modulated this innate signalling axis in CD4+ T cells to increase parasite-specific Th1 and diminish Tr1 cell responses. These findings identify STING as a critical mediator of Tr1 cell development during malaria.

immunology↗

bioRxiv2022

Potentiating the cross-reactive IFN-γ T cell and polyfunctional T cell responses by heterologous GX-19N DNA booster in mice primed with either a COVID-19 mRNA vaccine or inactivated vaccine

Waning vaccine-induced immunity, coupled with the emergence of SARS-CoV-2 variants, has inspired the widespread implementation of COVID-19 booster vaccinations. Here, we evaluated the potentials of the GX-19N DNA vaccine as a heterologous booster to enhance the protective immune response to SARS-CoV-2 in mice primed with either an inactivated virus particle (VP) or mRNA vaccine. We found that in the VP-primed condition, GX-19N enhanced the response of both vaccine-specific antibodies and cross-reactive T-cells to the SARS-CoV-2 variant of concern (VOC) compared to the homologous VP vaccine prime-boost. Under the mRNA-primed condition, GX-19N induced higher vaccine-induced T-cell responses but lower antibody responses than the homologous mRNA vaccine prime-boost. Furthermore, heterologous GX-19N boost induced higher S-specific polyfunctional CD4+ and CD8+ T cell responses than the homologous VP or mRNA prime-boost vaccinations. Our results provide new insights into booster vaccination strategies for the management of novel COVID-19 variants.

immunology↗

bioRxiv2022

Autophagic state prospectively identifies facultative stem cells in the intestinal epithelium

The intestinal epithelium exhibits a rapid and efficient regenerative response to injury. Emerging evidence supports a model where plasticity of differentiated cells, particularly those in the secretory lineages, contributes to epithelial regeneration upon ablation of injury-sensitive stem cells. However, such facultative stem cell activity is rare within secretory populations. Here we ask whether specific functional properties predict facultative stem cell activity. We utilize in vivo labeling combined with ex vivo organoid formation assays to evaluate how cell age and autophagic state contribute to facultative stem cell activity within secretory lineages. Strikingly, we find that cell age (time elapsed since cell cycle exit) does not correlate with secretory cell plasticity. Instead, high autophagic activity predicts plasticity and resistance to DNA damaging injury independently of cell lineage. Our findings indicate that autophagic status prior to injury serves as a lineageagnostic marker for the prospective identification of facultative stem cells.

cell biology↗

bioRxiv2021

Marked enhancement of neutralizing antibody and IFN-γ T-cell responses by GX-19N DNA booster in mice primed with inactivated vaccine

In response to the COVID-19 pandemic, an unprecedented level of vaccine development has occurred. As a result, various COVID-19 vaccines have been approved for use. Among these, inactivated virus particle (VP) vaccines have been widely used worldwide, but additional vaccination strategies are needed because of the short duration of immune responses elicited by these vaccines. Here, we evaluated homologous and heterologous prime-boost regimens using a VP vaccine and GX-19N DNA vaccine for their ability to enhance the protective immune response against SARS-CoV-2. We demonstrated that a heterologous prime-boost regimen with the VP vaccine and GX-19N DNA vaccine resulted in enhanced SRBD- & N-specific antibody responses, compared to the homologous VP vaccine prime-boost vaccination. In addition, the neutralizing antibody response was significantly improved with the heterologous VP prime-DNA boost regimen, and the neutralizing antibody induced with the heterologous prime-boost regimen did not decrease against the SARS-CoV-2 variant of concern (VOC). The heterologous VP prime-DNA boost regimen not only significantly increased S- and N-specific IFN-{gamma} T-cell responses, but also induced an equivalent level of T-cell response against SARS-CoV-2 VOCs. Our results provide new insights into prophylactic vaccination strategies for COVID-19 vaccination.

immunology↗

bioRxiv2021

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate theprogression of pancreatic cancer

Pancreatic cancer has the lowest survival rate in all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages. A better therapeutic development for this devastating disease is urgently needed. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm-/- mice. However, we found that Rhamm-/- mice expressed a truncated HMMR{Delta}exon8-16 protein at higher abundance levels than wild-type RHAMM. While HMMR{Delta}exon8-16 did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMR{Delta}exon8-16 was not apparent in these mice with short-life span. In addition, HMMR{Delta}exon8-16 shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMR{Delta}exon8- 16 that lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC) accelerated pancreatic cancer progression.

cancer biology↗

bioRxiv2020

A small increase in CHEK1 activity leads to the arrest of the first zygotic division in human

The first mitotic division in mammalian zygotes is unique. The fertilized egg reactivates its cell cycle, and the maternal and paternal genomes start to reprogram to become totipotent. The first division is very sensitive to a range of perturbations, particularly the DNA damage, leading to the embryo's failure to enter the first mitosis. We discovered that a point mutation in the human CHEK1 gene resulted in an Arginine 442 to Glutamine change at the C-terminus of the CHEK1 protein. CHEK1 R442Q mutation caused the zygote to arrest just before the first division. Heterozygote individuals appeared to be healthy except that the female carriers are infertile. Expressing the corresponding mouse mutant Chk1 protein in zygotes also caused arrest before the first mitosis. Treating Chk1 R442Q mouse zygotes with low concentrations of CHEK1 inhibitor enabled the embryos to overcome the cell cycle arrest and resume normal development. Our results revealed an unexpected zygote mitotic checkpoint, which is extremely sensitive to the CHEK1 kinase activity. The fine-tuning of the DNA damage checkpoint permits the arrested one-cell embryos to overcome the first mitotic block and develop into healthy animals. These findings have important implications in assisted human reproduction.

developmental biology↗

bioRxiv2020

Transcriptional control of apical protein clustering drives de novo cell polarity establishment in the early mouse embryo

The establishment of cell polarity de novo in the early mammalian embryo triggers the transition from totipotency to differentiation to generate embryonic and extra-embryonic lineages. However, the molecular mechanisms governing the timing of cell polarity establishment remain unknown. Here, we identify stage-dependent transcription of Tfap2c and Tead4 as well as Rho GTPase signaling as key for the onset of cell polarization. Importantly, advancing their activity can induce precocious cell polarization and ectopic lineage differentiation in a cell-autonomous manner. Moreover, we show that the asymmetric clustering of apical proteins, regulated by Tfap2c-Tead4, and not actomyosin flow, mediates apical protein polarization. These findings identify the long-sought mechanism for the onset of polarization and the first lineage segregation in the mouse embryo.

developmental biology↗