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in category developmental biology
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103 downloads developmental biology
Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output. Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a mutant heart as a possible consequence of Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1α) activation, consistent with a recent intriguing report that CoQ may function as a natural ligand and partial agonist of Peroxisome Proliferator-Activated Receptor (PPAR) α/γ. Taken together, our study reveals a previously unknown function of a novel striated muscle-enriched mitochondrial protein Coq10a in regulating postnatal heart growth.
102 downloads developmental biology
The cell cycle regulator p27Kip1 is a critical factor controlling cell number in many lineages. While its anti-proliferative effects are well-established, the extent to which this is a result of its function as a cyclin-dependent kinase (CDK) inhibitor or through other known molecular interactions is not clear. To genetically dissect its role in the developing corneal endothelium, we examined mice harboring two loss-of-function alleles, a null allele ( p27- ) that abrogates all protein function and a knockin allele ( p27CK- ) that targets only its interaction with cyclins and CDKs. Whole-animal mutants, in which all cells are either homozygous knockout or knockin, exhibit identical proliferative increases (~0.6-fold) compared with wild-type tissues. On the other hand, use of mosaic analysis with double markers (MADM) to produce infrequently-occurring clones of wild-type and mutant cells within the same tissue environment uncovers a roughly three- and six-fold expansion of individual p27CK-/CK- and p27-/- cells, respectively. Mosaicism also reveals distinct migration phenotypes, with p27-/- cells being highly restricted to their site of production and p27CK-/CK- cells more widely scattered within the endothelium. Using a density-based clustering algorithm to quantify dispersal of MADM-generated clones, a four-fold difference in aggregation is seen between the two types of mutant cells. Overall, our analysis reveals that, in developing mouse corneal endothelium, p27 regulates cell number by acting cell autonomously, both through its interactions with cyclins and CDKs and through a cyclin-CDK-independent mechanism(s). Combined with its parallel influence on cell motility, it constitutes a potent multi-functional effector mechanism with major impact on tissue organization.
101 downloads developmental biology
Maternal malnutrition and micronutrient deficiencies can alter fetal development. However, the mechanisms underlying these relationships are poorly understood. A systems-approach was used to investigate the effects of malnutrition on maternal gut microbes and folate/inositol transport in the maternal/fetal gut and placenta. Female mice were fed a control diet (CON) diet, undernourished (UN, restricted by 30% of CON intake) or a high fat diet (HF, 60% kcals fat) during pregnancy. At gestational day 18.5 we assessed circulating folate levels by microbiological assay, relative abundance of gut lactobacilli by G3PhyloChip™, and folate/inositol transporters in placenta and maternal/fetal gut by qPCR/immunohistochemistry. UN and HF-fed mothers had lower plasma folate concentrations vs. CON. Relative abundance of three lactobacilli taxa were higher in HF vs. UN and CON. HF-fed mothers had higher gut Pcft and Rfc1 , and lower Smit2 , mRNA expression vs. UN and CON. HF placentae had increased Fr β expression vs. UN. mRNA expression of Pcft , Frα and Smit2 was higher in gut of HF fetuses vs. UN and CON. Transporter protein expression was not different between groups. Maternal malnutrition alters select gut microbes and folate/inositol transporters, which may influence maternal micronutrient status and delivery to the fetus, impacting pregnancy and fetal outcomes.
99 downloads developmental biology
Rafael Vilar Sampaio, Juliano Rodrigues Sangalli, Tiago HC De Bem, Dewison Ricardo Ambrizi, Maite del Collado, Alessandra Bridi, Ana CFCM Avila, Carolina Habermann Macabelli, Lilian Jesus Oliveira, Juliano Coelho da Silveira, Marcos R. Chiaratti, Felipe Perecin, Fabiana Fernandes Bressan, Lawrence Charles Smith, Pablo Juan Ross, Flavio Vieira Meirelles
Orchestrated events, including extensive changes in epigenetic marks, allow a somatic nucleus to become totipotent after transfer into an oocyte, a process termed nuclear reprogramming. Recently, several strategies have been applied in order to improve reprogramming efficiency, mainly focused on removing repressive epigenetic marks such as histone methylation from the somatic nucleus. Herein we used the specific and non-toxic chemical probe UNC0638 to inhibit the catalytic activity of the histone metyltransferases EHMT1 and EHMT2. Either the donor cell (before reconstruction) or the early embryo was exposed to the probe to assess its effect on developmental rates and epigenetic marks. First, we showed that the treatment of bovine fibroblasts with UNC0638 did mitigate the levels of H3K9me2. Moreover, H3K9me2 levels were decreased in cloned embryos regardless of treating either donor cells or early embryos with UNC0638. Additional epigenetic marks such as H3K9me3, 5mC, and 5hmC were also affected by the UNC0638 treatment. Therefore, the use of UNC0638 did diminish the levels of H3K9me2 and H3K9me3 in SCNT-derived blastocysts, but this was unable to improve their preimplantation development. These results indicate that the specific reduction of H3K9me2 by inhibiting EHMT1/2 causes diverse modifications to the chromatin during early development, suggesting an intense epigenetic crosstalk during nuclear reprogramming.
99 downloads developmental biology
Pluripotent stem cells (PSCs) exist in a unique state poised to differentiate into any of the somatic cell types in part by maintaining an open chromatin structure. How these extraordinary cells suppress spurious transcription in the relative absence of repressive epigenetic modifications is poorly understood. PSCs are depleted for transcriptional elongation associated epigenetic modifications, primarily H3K79me2. Although H3K79me2 is found on thousands of genes, inhibiting the enzymatic activity of its methyltransferase, Dot1L results in few transcriptional changes, the majority of which are upregulated. During reprogramming of somatic cells to pluripotency, Dot1L inhibition (Dot1Li) at the midpoint is particularly effective at yielding greater number of colonies. Further, Dot1Li enhances reprogramming beyond early phases such as the mesenchymal to epithelial transition and from already epithelial cell types such as keratinocytes. Modulation of single genes from the DotLi transcriptional response cannot replace its function. Significantly, Dot1L inhibition does not enhance lineage conversion to neurons. Taken together, our results indicate that H3K79me is not a universal barrier of cell fate transitions but specifically protects cells from reverting to the pluripotent state.
98 downloads developmental biology
Geoffrey M.W. Cook, Catia Sousa, Julia Schaeffer, Katherine Wiles, Prem Jareonsettasin, Asanish Kalyanasundaram, Eleanor Walder, Catharina Casper, Serena Patel, Pei Wei Chua, Gioia Riboni-Verri, Mansoor Raza, Nol Swaddiwudhipong, Andrew Hui, Ameer Abdullah, Saj Wajed, Roger J. Keynes
Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.
98 downloads developmental biology
The reaction of twenty four hour old primitive streak chick embryoblasts exposed to epidermal growth factor was compared with non-exposed controls. After 24-36 hours incubation, proliferation up to 5-6 cell layers in thickness of the epiblast-hypoblast layers was evident in the EGF exposed embryo blasts. This compared with the normally expected one cell layer in thickness at this stage of development.
98 downloads developmental biology
During kidney development, WNT/β-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of renal stem cells. Here we show that the two signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/β-catenin signallingand their genetic deletion leads to a rapid decline of renal progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss of Bmp7 expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activate Lef1, Fgf8 and Wnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of R-spondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and reveal Lgr -dependent and independent functions for these ligands during kidney formation.
97 downloads developmental biology
Many studies have focused on the mechanisms of stem cell maintenance via their interaction with a particular niche or microenvironment in adult tissues, but how formation of a functional niche is initiated, including how stem cells within a niche are established, is less well understood. Adult Drosophila melanogaster ovary Germline Stem Cell (GSC) niches are comprised of somatic cells forming a stack called a Terminal Filament (TF) and underlying Cap Cells (CCs) and Escort Cells (ECs), which are in direct contact with GSCs. In the adult, the Engrailed (En) transcription factor is specifically expressed in niche cells where it directly controls expression of the decapentaplegic gene (dpp) encoding a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules, which are key factors for GSC maintenance. In late third instar larval ovaries, in response to BMP signaling from newly formed niches, adjacent primordial germ cells become GSCs. The bric-a-brac paralogs (bab1 and bab2) encode BTB/POZ-domain containing transcription factors that are also expressed in developing GSCs niches where they are required for TF formation. Here, we demonstrate that Bab1 and Bab2 display redundant cell autonomous function for TF morphogenesis and we identify a new function for these genes in GSC establishment. Moreover, we show that Bab proteins control dpp expression in otherwise correctly specified CCs, independently of En and its paralog Invected (Inv). In fact, our results also indicate that en/inv function in larval stages are neither essential for TF formation, nor GSC establishment. Finally, when bab2 was overexpressed in ovarian somatic cells outside of the niche, where en/inv were not expressed, ectopic BMP signaling activation was induced in adjacent germ cells of adult ovaries, which formed GSC-like tumors. Together, these results indicate that Bab transcription factors are positive regulators of BMP signaling for acquisition of GSC status.
97 downloads developmental biology
Abstract Background : Though menstruation is normal physiology in the females' life, if not managed safely, it can interrupt daily activity or it may lead to health problems. Poor water, sanitation and hygiene (WASH) facilities in schools, inadequate puberty education and lack of hygienic menstrual hygiene management items (absorbents) cause girls to experience menstruation as shameful and uncomfortable. This study aimed to assess the extent of unsafe menstrual hygiene practice and factors influencing it among school females in Ambo, Ethiopia. Methods : an institutional-based mixed-method cross-sectional study was conducted from March 01 to 15/2018 to collect data from 364 school females, teachers, and investigators observation. To collect the data, self-administered technique, interview, observational and FGD techniques were used. Data were analyzed using SPSS statistical software version 20. Uni-variate, bivariate and multiple logistic regression analysis were done. With 95% CI, the P-value of less than 0.05 was taken as the level of significance. Results : the prevalence of the unsafe menstrual hygiene management practice was 53.6%, which implies urgent response from the stakeholders is of paramount importance. Factors such as the age of the females, frequency of discussing menses with mothers and source of information about menses were variables significantly associated with menstrual hygiene management practice. Conclusion and Recommendation: High numbers of school females' menstrual hygiene management were poorly managed. This implies urgent measure is needed from the stakeholders to solve these problems so that sustainable development goal number 3, 4 and 5 will be achieved. To rid off the current problems which school females are facing, comprehensive and different sectors collaboration is important. Specifically, education sectors, water and sanitation sectors, and health sectors bear the front-line responsibilities.
96 downloads developmental biology
Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous male patients, a phenomenon called cellular interference that is correlated with cell segregation resulting from EPHRIN-B1 mosaicism. Efnb1 heterozygous mutant mice also exhibit more severe phenotypes than Efnb1 hemizygous males as well as cell segregation, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse models to elucidate mechanisms underlying CFNS pathogenesis. By generating ephrin-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that ephrin-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, tissue-specific disruption of Efnb1 throughout neural development does not appear to contribute to CFNS dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. Ephrin-B1 can bind and signal with EphB1, EphB2, and EphB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EphB2 and EphB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EphB1-3 does not recapitulate CFNS-like Efnb1 heterozygous severity. Finally, by generating Efnb1+/-; Ephb1; Ephb2; Ephb3 quadruple knockout mice, we determine how modulating cumulative receptor activity influences cell segregation in craniofacial development and find that while EphB2 and EphB3 play an important role in craniofacial cell segregation, EphB1 is more important for cell segregation in the brain; surprisingly, complete loss of EphB1-EphB3 does not completely abrogate cell segregation. Together, these data advance our understanding of the morphogenetic etiology and signaling interactions underlying CFNS dysmorphology.
96 downloads developmental biology
Govindkumar Balagannavar, Kavyashree Basavaraju, Akhilesh Kumar Bajpai, Sravanthi Davuluri, Shruthi Kannan, Vasan S S, Madhusudhan M, Darshan Chandrashekar, Neelima Chitturi, Vashishtkumar Balagannavar, Sailaja Oguru, Kshitish K Acharya
Studying the molecular basis of Non-Obstructive Azoospermia (NOA), a case of failed spermatogenesis at various stages, can also help in exploring molecular basis of human spermatogenesis and possibly pave way to identify new targets for male contraceptive development. Hence, we initiated a functional genomics study by applying RNA-seq. Testicular biopsies collected from donors with Non-Obstructive Azoospermia (NOA), Obstructive Azoospermia (OA), Congenital Bilateral Absence of the Vas Deferens (CBAVD), and Varicocele (VA) conditions. Strong association of 100+ genes with human spermatogenesis and NOA has been detected via NGS-based transcriptomic analysis. In addition, 20 RNA molecules have been short-listed for potential diagnostic applications (non-obstructive azoospermia vs. obstructive azoospermia, varicocele or normal). A hierarchical list of several genes and alternatively spliced mRNAs, transcribed differentially in NOA, is reported - based on a 'strength of association'. Such association with NOA, spermatogenesis or both is a new finding for many genes as revealed by a comparison with a newly prepared comprehensive list of genes having such association with human spermatogenesis/NOA. Many top-ranking genes involved in viral gene expression were up-regulated in testes from NOA-patients, while those associated with an antiviral mechanism were down-regulated. A tangential finding: while most well-established control mRNAs did not qualify, two new ones worked best in RT-qPCR experiments. Needle-aspiration of testicular biopsies, followed by the use of short-listed promising candidate biomarkers (i.e., 16 mRNA & 4 chimeric transcripts) and control mRNAs in RT-qPCR-based diagnostic assays, may help to avoid open surgeries in future.
96 downloads developmental biology
Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO. Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation. RXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls. This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models. * EO : endochondral ossification RXR : retinoid x receptor SOX9 : sex determining region-box 9 RUNX2 : runt-related transcription factor 2 MEF2C : myocyte enhancer factor–2c PPAR : peroxisome proliferator-activated receptor FXR : farnesoid x receptor LXR : liver x receptor RAR : retinoic acid receptor VDR : vitamin d receptor TR : thyroid receptor IP : intraperitoneal DMSO : dimethyl sulfoxide GLP : glucagon-like peptide MEM : minimum essential medium eagle TRAP : tartrate resistant acid phosphatase TUNEL : terminal deoxynucleotidyl transferase dUTP nick end labelling PCNA : proliferating cell nuclear antigen RANKL : receptor activator of nuclear factor of kappa-B ligand
96 downloads developmental biology
Transcription factor autoregulation is a simple network motif (recurring circuit) built into genetic regulatory networks that direct cell behavior. Negative autoregulation (NAR) network motifs are particularly abundant in bacteria and provide specific functions, such as buffering against transcriptional noise. Here, we investigate the phenotypic consequence of perturbing NAR of a major transcription factor, MrpC, that controls the multicellular development program of the bacterium Myxococcus xanthus. Launch of the developmental program directs certain cells in the population to first aggregate into haystack-shaped mounds, and then to differentiate into environmentally resistant spores to form mature fruiting bodies. Perturbation of MrpC NAR causes a striking phenotype in which cells lose synchronized transition from aggregation to sporulation. Instead, some cells abruptly exit aggregation centers and remain locked in a cohesive swarming state, while the remaining cells transition to spores inside residual fruiting bodies. As predicted, disruption of MrpC NAR led to an increased and broadened population distribution of mrpC expression. Examination of MrpC levels in developmental subpopulations during in situ development demonstrated cells locked in the swarms contained intermediate MrpC levels insufficient to promote sporulation. These results suggest an inherent property of NAR motifs that function in multicellular developmental programs is to facilitate synchronized responses.
95 downloads developmental biology
Sarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown of Drosophila Cofilin (DmCFL), an actin depolymerizing factor, disrupts both sarcomere structure and muscle function. Loss of DmCFL also results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. Strikingly, activation of the proteasome delayed muscle deterioration in our model. Further, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans, affects CFL function and leads to the muscle phenotypes observed in vivo. Our data provide significant insights to the role of CFLs during sarcomere formation as well as mechanistic implications for disease progression in NM patients.
94 downloads developmental biology
Wnt/FZD signalling activity is required for spinal cord development, including the dorsal-ventral patterning of the neural tube, where it affects proliferation and specification of neurons. Wnt ligands initiate canonical, β-catenin-dependent, signaling by binding to Frizzled receptors. However, in many developmental contexts the cognate FZD receptor for a particular Wnt ligand remains to be identified. Here, we characterized FZD10 expression in the dorsal neural tube where it overlaps with both Wnt1 and Wnt3a, as well as markers of dorsal progenitors and interneurons. We show FZD10 expression is sensitive to Wnt1, but not Wnt3a expression, and FZD10 plays a role in neural tube patterning. Knockdown approaches show that Wnt1 induced ventral expansion of dorsal neural markes, Pax6 and Pax7, requires FZD10. In contrast, Wnt3a induced dorsalization of the neural tube is not affected by FZD10 knockdown. Gain of function experiments show that FZD10 is not sufficient on its own to mediate Wnt1 activity in vivo . Indeed excess FZD10 inhibits the dorsalizing activity of Wnt1. However, addition of the Lrp6 co-receptor dramatically enhances the Wnt1/FZD10 mediated activation of dorsal markers. This suggests that the mechanism by which Wnt1 regulates proliferation and patterning in the neural tube requires both FZD10 and Lrp6.
94 downloads developmental biology
Eye absent (Eya) is a protein which has been structurally conserved from hydrozoans to humans which has two functions: it is both a transcription cofactor and a protein tyrosine phosphatase. Eya was first described in the fly Drosophila melanogaster for its role in eye development, and the same functions were also later reported in less derived insects. Studies on the involvement of Eya in insect oogenesis are limited to D. melanogaster, which has meroistic ovaries. In this fly, Eya plays a fundamental role in the first stages of ovarian development because Eya mutations abolish gonad formation. In this present work we studied the function of Eya in the panoistic ovary of the cockroach Blattella germanica. We demonstrated that Eya is essential for correct ovary development also in this ovary type. In B. germanica ovaries, Eya affects both somatic and germinal cells in the germarium and the vitellarium, acting differently in different ovarian regions. Development of the basal ovarian follicles is arrested BgEya-depleted females, while in the germaria, BgEya helps to the maintain the correct number of somatic and germinal stem cells by regulating the expression of ecdysteroidogenic genes in the ovary.
94 downloads developmental biology
Among the flowering plants, the gametophyte development and reproductive biology of orchids is particularly poorly understood. Cypripedium japonicum is a perennial herb, native to East Asia. Due to its limited distribution, the species is included in the Endangered category of the IUCN Red List. Light microscopy and SEM methods were used to study the development of the gametes and embryo. The complete reproductive cycle was developed based on our observations. Anther development begins under the soil and meiosis of pollen cells begins 3 weeks before anthesis, possibly during early April. The megaspore mother cells develop just after pollination in early May and mature in mid-late June. The pattern of embryo sac formation is bisporic and there are six nuclei. Triple fertilization results in the endosperm nucleus. A globular embryo is formed after multiple cell division and 9 weeks after pollination the entire embryo sac is occupied by embryo. Overall comparisons of the features of gametophyte and embryo development in C. japonicum suggest that previous reports on the embryology of Cypripedium are not sufficient to characterize the entire genus. Based on the available information a reproductive calendar showing the key reproductive events leading to embryo formation has been prepared.
93 downloads developmental biology
The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 reciprocal regulatory pathway is critical for vertebral specification. Lin28a-/- mice exhibited homeotic transformations of vertebrae which were caused by the global dysregulation of posterior Hox genes. The accumulation of let-7-family microRNAs in Lin28a-/- mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7-family microRNAs. These results suggest that Lin28/let-7 pathway is possibly involved in the modulation of the 'Hox code' via Polycomb regulation during axial patterning in vertebrates.
92 downloads developmental biology
There is currently an imbalance between the supply and demand of functional red blood cells (RBCs) in clinical applications, and this imbalance can be addressed by regenerating RBCs with a variety of in vitro methods. Induced pluripotent stem cells (iPSCs) can address the low supply of cord blood and the ethical issues in embryonic stem cell research and provide a promising strategy to eliminate immune rejection. However, no complete single-cell level differentiation pathway exists for the iPSC-derived RBC differentiation system. In this study, we used iPSC line BC1 to establish an RBC regeneration system and used the 10x Genomics single-cell transcriptome platform to map the cell lineage and differentiation trajectories on day 14 (D14) of the regeneration system. We found iPSC differentiation was not synchronized during embryoid body (EB) culture, and the D14 cells in the system mainly consisted of mesodermal and various blood cells, similar to yolk sac hematopoiesis. During asynchronous EB differentiation, iPSCs undergo three bifurcations before they enter erythroid differentiation, and the driver genes of each bifurcation were identified. The key roles of cell adhesion and estradiol in RBC regeneration were observed. This study provides systematically theoretical guidance for the optimization of the iPSC-derived RBC differentiation system.
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