Development Growth & Differentiation最新文献

Suzuki, M., Nukazuka, A., Kamei, Y., Yuba, S., Oda, Y., & Takagi, S. (2022). Mosaic gene expression analysis of semaphorin–plexin interactions in Caenorhabditis elegans using the IR-LEGO single-cell gene induction system. Development, Growth & Differentiation, 64(5), 230–242. https://doi.org/10.1111/dgd.12793.

In the fifth sentence of the “Abstract” section, the word “semaphoring” should be “semaphorin.” The sentence should have read:

“Here, we applied IR-LEGO to examine the cell–cell interactions mediated by semaphorin–plexin signaling in Caenorhabditis elegans by inducing wild-type semaphorin/plexin in single cells within the population of mutant cells lacking the relevant proteins.”

We apologize for this error.

Urinary bladder organogenesis requires coordinated cell growth, specification, and patterning of both mesenchymal and epithelial compartments. Tcf21, a gene that encodes a helix–loop–helix transcription factor, is specifically expressed in the mesenchyme of the bladder during development. Here we show that Tcf21 is required for normal development of the bladder. We found that the bladders of mice lacking Tcf21 were notably hypoplastic and that the Tcf21 mutant mesenchyme showed increased apoptosis. There was also a marked delay in the formation of visceral smooth muscle, accompanied by a defect in myocardin (Myocd) expression. Interestingly, there was also a marked delay in the formation of the basal cell layer of the urothelium, distinguished by diminished expression of Krt5 and Krt14. Our findings suggest that Tcf21 regulates the survival and differentiation of mesenchyme cell-autonomously and the maturation of the adjacent urothelium non-cell-autonomously during bladder development.

Skeletal tissues including cartilage and bones are characteristic features of vertebrates that are crucial for supporting body morphology and locomotion. Studies mainly in mice have shown that osteoblasts and chondroblasts are supplied from several progenitors like the sclerotome cells in the embryonic stage, osteo-chondroprogenitors in growing long bones, and skeletal stem cells of bone marrow in the postnatal period. However, the exact origins of progenitor cells, their lineage relationships, and their potential to differentiate into osteoblasts and chondroblasts from embryos to adult tissues are not well understood. In this study, we conducted clonal cell tracking in zebrafish and showed that sox9a⁺ cells are already committed to either chondrogenic or osteogenic fates during embryonic stages and that respective progenies are independently maintained as mesenchymal progenitor pools. Once committed, they never change their lineage identities throughout animal life, even through regeneration. In addition, we further revealed that only osteogenic mesenchymal cells replenish the osteoblast progenitor cells (OPCs), a population of reserved tissue stem cells found to be involved in the de novo production of osteoblasts during regeneration and homeostasis in zebrafish. Thus, our clonal cell tracking study in zebrafish firstly revealed that the mesenchymal progenitor cells that are fated to develop into either chondroblasts or osteoblasts serve as respective tissue stem cells to maintain skeletal tissue homeostasis. Such mesenchymal progenitors dedicated to producing either chondroblasts or osteoblasts would be important targets for skeletal tissue regeneration.

Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.

During development, progenitor cell survival is essential for proper tissue functions, but the underlying mechanisms are not fully understood. Here we show that ERCC6L2, a member of the Snf2 family of helicase-like proteins, plays an essential role in the survival of developing chick neural cells. ERCC6L2 expression is induced by the Sonic Hedgehog (Shh) signaling molecule by a mechanism similar to that of the known Shh target genes Ptch1 and Gli1. ERCC6L2 blocks programmed cell death induced by Shh inhibition and this inhibition is independent of neural tube patterning. ERCC6L2 knockdown by siRNA resulted in the aberrant appearance of apoptotic cells. Furthermore, ERCC6L2 cooperates with the Shh signal and plays an essential role in the induction of the anti-apoptotic factor Bcl-2. Taken together, ERCC6L2 acts as a key factor in ensuring the survival of neural progenitor cells.

The establishment of animal models for Parkinson's disease (PD) has been challenging. Nevertheless, once established, they will serve as valuable tools for elucidating the causes and pathogenesis of PD, as well as for developing new strategies for its treatment. Following the recent discovery of a series of PD causative genes in familial cases, teleost fishes, including zebrafish and medaka, have often been used to establish genetic PD models because of their ease of breeding and gene manipulation, as well as the high conservation of gene orthologs. Some of the fish lines can recapitulate PD phenotypes, which are often more pronounced than those in rodent genetic models. In addition, a new experimental teleost fish, turquoise killifish, can be used as a sporadic PD model, because it spontaneously manifests age-dependent PD phenotypes. Several PD fish models have already made significant contributions to the discovery of novel PD pathological features, such as cytosolic leakage of mitochondrial DNA and pathogenic phosphorylation in α-synuclein. Therefore, utilizing various PD fish models with distinct degenerative phenotypes will be an effective strategy for identifying emerging facets of PD pathogenesis and therapeutic modalities.

Research in neuroscience has greatly benefited from the development of genetic approaches that enable lineage tracing, cell type targeting, and conditional gene regulation. Recent advances in combinatorial strategies, which integrate multiple cellular features, have significantly enhanced the spatiotemporal precision and flexibility of these manipulations. In this minireview, we introduce the concept and design of these strategies and provide a few examples of their application in genetic fate mapping, cell type targeting, and reversible conditional gene regulation. These advancements have facilitated in-depth investigation into the developmental principles underlying the assembly of brain circuits, granting experimental access to highly specific cell lineages and subtypes, as well as offering valuable new tools for modeling and studying neurological diseases. Additionally, we discuss future directions aimed at expanding and improving the existing genetic toolkit for a better understanding of the development, structure, and function of healthy and diseased brains.

We previously identified Xenopus tudor domain containing 6/Xenopus tudor repeat (Xtdrd6/Xtr), which was exclusively expressed in the germ cells of adult Xenopus laevis. Western blot analysis showed that the XTdrd6/Xtr protein was translated in St. I/II oocytes and persisted as a maternal factor until the tailbud stage. XTdrd6/Xtr has been reported to be essential for the translation of maternal mRNA involved in oocyte meiosis. In the present study, we examined the distribution of the XTdrd6/Xtr protein during oogenesis and early development, to predict the time point of its action during development. First, we showed that XTdrd6/Xtr is localized to germinal granules in the germplasm by electron microscopy. XTdrd6/Xtr was found to be localized to the origin of the germplasm, the mitochondrial cloud of St. I oocytes, during oogenesis. Notably, XTdrd6/Xtr was also found to be localized around the nuclear membrane of St. I oocytes. This suggests that XTdrd6/Xtr may immediately interact with some mRNAs that emerge from the nucleus and translocate to the mitochondrial cloud. XTdrd6/Xtr was also detected in primordial germ cells and germ cells throughout development. Using transgenic Xenopus expressing XTdrd6/Xtr with a C-terminal FLAG tag produced by homology-directed repair, we found that the zygotic translation of the XTdrd6/Xtr protein began at St. 47/48. As germ cells are surrounded by gonadal somatic cells and are considered to enter a new differentiation stage at this phase, the newly synthesized XTdrd6/Xtr protein may regulate the translation of mRNAs involved in the new steps of germ cell differentiation.

Abnormal expression of the transcriptional regulator and hedgehog (Hh) signaling pathway effector Gli3 is known to trigger congenital disease, most frequently affecting the central nervous system (CNS) and the limbs. Accurate delineation of the genomic cis-regulatory landscape controlling Gli3 transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in Gli3 intronic intervals (CNE15–21). Transgenic assays in zebrafish revealed that most of these elements drive activities in Gli3 expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage-specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14/hs1586) indicates co-option of limb specificity from other tissues prior to the divergence of amniotes and lobe-finned fish. These results uncover a novel subset of intronic Gli3 enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.

Neural stem cells are multipotent stem cells that generate functional newborn neurons through a process called neurogenesis. Neurogenesis in the adult brain is tightly regulated and plays a pivotal role in the maintenance of brain function. Disruption of adult neurogenesis impairs cognitive function and is correlated with numerous neurologic disorders. Deciphering the mechanisms underlying adult neurogenesis not only advances our understanding of how the brain functions, but also offers new insight into neurologic diseases and potentially contributes to the development of effective treatments. The field of adult neurogenesis is experiencing significant growth in China. Chinese researchers have demonstrated a multitude of factors governing adult neurogenesis and revealed the underlying mechanisms of and correlations between adult neurogenesis and neurologic disorders. Here, we provide an overview of recent advancements in the field of adult neurogenesis due to Chinese scientists.