Differentiation最新文献

{"title":"Androgenic induction of penile features in postnatal female mouse external genitalia from birth to adulthood: Is the female sexual phenotype ever irreversibly determined?","authors":"Gerald R. Cunha,&nbsp;Mei Cao,&nbsp;Amber Derpinghaus,&nbsp;Laurence S. Baskin","doi":"10.1016/j.diff.2023.02.001","DOIUrl":"10.1016/j.diff.2023.02.001","url":null,"abstract":"<div><p>Female mice were treated for 35 days from birth to 60 days postnatal (P0, [birth], P5, P10, P20 and adult [∼P60]) with dihydrotestosterone (DHT). Such treatment elicited profound masculinization the female external genitalia and development of penile features (penile spines, male urogenital mating protuberance (MUMP) cartilage, corpus cavernosum glandis, corporal body, MUMP-corpora cavernosa, a large preputial space, internal preputial space, os penis). Time course studies demonstrated that DHT elicited canalization of the U-shaped clitoral lamina to create a U-shaped preputial space, preputial lining epithelium and penile epithelium adorned with spines. The effect of DHT was likely due to signaling through androgen receptors normally present postnatally in the clitoral lamina and associated mesenchyme. This study highlights a remarkable male/female difference in specification and determination of urogenital organ identity. Urogenital organ identity in male mice is irreversibly specified and determined prenatally (prostate, penis, and seminal vesicle), whereas many aspects of the female urogenital organogenesis are not irreversibly determined at birth and in the case of external genitalia are not irreversibly determined even into adulthood, the exception being positioning of the female urethra, which is determined prenatally.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9676074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sf3b4 regulates chromatin remodeler splicing and Hox expression","authors":"Shruti Kumar ,&nbsp;Sabrina Shameen Alam ,&nbsp;Eric Bareke ,&nbsp;Marie-Claude Beauchamp ,&nbsp;Yanchen Dong ,&nbsp;Wesley Chan ,&nbsp;Jacek Majewski ,&nbsp;Loydie A. Jerome-Majewska","doi":"10.1016/j.diff.2023.04.004","DOIUrl":"10.1016/j.diff.2023.04.004","url":null,"abstract":"<div><p>SF3B proteins form a heptameric complex in the U2 small nuclear ribonucleoprotein, essential for pre-mRNA splicing. Heterozygous pathogenic variants in human <em>SF3B4</em> are associated with head, face, limb, and vertebrae defects. Using the CRISPR/Cas9 system, we generated mice with constitutive heterozygous deletion of <em>Sf3b4</em> and showed that mutant embryos have abnormal vertebral development. Vertebrae abnormalities were accompanied by changes in levels and expression pattern of <em>Ho</em>x genes in the somites. RNA sequencing analysis of whole embryos and somites of <em>Sf3b4</em> mutant and control litter mates revealed increased expression of other <em>Sf3b4</em> genes. However, the mutants exhibited few differentially expressed genes and a large number of transcripts with differential splicing events (DSE), predominantly increased exon skipping and intron retention. Transcripts with increased DSE included several genes involved in chromatin remodeling that are known to regulate <em>Hox</em> expression. Our study confirms that <em>Sf3b4</em> is required for normal vertebrae development and shows, for the first time, that like <em>Sf3b1</em>, <em>Sf3b4</em> also regulates <em>Hox</em> expression. We propose that abnormal splicing of chromatin remodelers is primarily responsible for vertebral defects found in <em>Sf3b4</em> heterozygous mutant embryos.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9678843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant","authors":"David Paz ,&nbsp;Briana E. Pinales ,&nbsp;Barbara S. Castellanos ,&nbsp;Isaiah Perez ,&nbsp;Claudia B. Gil ,&nbsp;Lourdes Jimenez Madrigal ,&nbsp;Nayeli G. Reyes-Nava ,&nbsp;Victoria L. Castro ,&nbsp;Jennifer L. Sloan ,&nbsp;Anita M. Quintana","doi":"10.1016/j.diff.2023.04.003","DOIUrl":"10.1016/j.diff.2023.04.003","url":null,"abstract":"<div><p>Variants in the <em>MMACHC</em> gene cause combined methylmalonic acidemia and homocystinuria <em>cblC</em> type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. <em>cblC</em> is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of <em>Mmachc</em> deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. <em>MMACHC</em> encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as <em>cblX</em> syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in <em>cblX</em> syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in <em>MMACHC</em> cause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of <em>cblC</em> (<em>hg13</em>) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, <em>sox10</em> (RFP transgene) or <em>barx1</em>. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of <em>MMACHC</em> causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9704723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ordered deployment of distinct ciliary beating machines in growing axonemes of vertebrate multiciliated cells","authors":"Chanjae Lee,&nbsp;Yun Ma,&nbsp;Fan Tu,&nbsp;John B. Wallingford","doi":"10.1016/j.diff.2023.03.001","DOIUrl":"10.1016/j.diff.2023.03.001","url":null,"abstract":"<div><p>The beating of motile cilia requires the coordinated action of diverse machineries that include not only the axonemal dynein arms, but also the central apparatus, the radial spokes, and the microtubule inner proteins. These machines exhibit complex radial and proximodistal patterns in mature axonemes, but little is known about the interplay between them during motile ciliogenesis. Here, we describe and quantify the relative rates of axonemal deployment for these diverse cilia beating machineries during the final stages of differentiation of <em>Xenopus</em> epidermal multiciliated cells.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523804/pdf/nihms-1932997.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9676115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of hedgehog signaling leads to hyoid bone dysplasia during embryogenesis","authors":"Yan Guo ,&nbsp;Xingyu Chen ,&nbsp;Yongzhen Lai ,&nbsp;Meng Lu ,&nbsp;Chengyong Wang ,&nbsp;Yun Shi ,&nbsp;Chengyan Ren ,&nbsp;Weihui Chen","doi":"10.1016/j.diff.2023.05.001","DOIUrl":"10.1016/j.diff.2023.05.001","url":null,"abstract":"<div><p>The development of the hyoid bone is a complex process that involves the coordination of multiple signaling pathways. Previous studies have demonstrated that disruption of the hedgehog pathway in mice results in a series of structural malformations. However, the specific role and critical period of the hedgehog pathway in the early development of the hyoid bone have not been thoroughly characterized. In this study, we treated pregnant ICR mice with the hedgehog pathway inhibitor vismodegib by oral gavage in order to establish a model of hyoid bone dysplasia. Our results indicate that administration of vismodegib at embryonic days 11.5 (E11.5) and E12.5 resulted in the development of hyoid bone dysplasia. We were able to define the critical periods for the induction of hyoid bone deformity through the use of a meticulous temporal resolution. Our findings suggest that the hedgehog pathway plays a crucial role in the early development of the hyoid bone. Additionally, our research has established a novel and easily established mouse model of synostosis in the hyoid bone using a commercially available pathway-selective inhibitor.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9669823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fgf8 promotes survival of nephron progenitors by regulating BAX/BAK-mediated apoptosis","authors":"Matthew J. Anderson ,&nbsp;Salvia Misaghian ,&nbsp;Nirmala Sharma ,&nbsp;Alan O. Perantoni ,&nbsp;Mark Lewandoski","doi":"10.1016/j.diff.2022.12.001","DOIUrl":"10.1016/j.diff.2022.12.001","url":null,"abstract":"<div><p>Fibroblast growth factors (<em>Fgfs</em>) have long been implicated in processes critical to embryonic development, such as cell survival, migration, and differentiation. Several mouse models of organ development ascribe a prosurvival requirement specifically to FGF8. Here, we explore the potential role of prosurvival FGF8 signaling in kidney development. We have previously demonstrated that conditional deletion of <em>Fgf8</em> in the mesodermal progenitors that give rise to the kidney leads to renal aplasia in the mutant neonate. Deleterious consequences caused by loss of FGF8 begin to manifest by E14.5 when massive aberrant cell death occurs in the cortical nephrogenic zone in the rudimentary kidney as well as in the renal vesicles that give rise to the nephrons. To rescue cell death in the <em>Fgf8</em> mutant kidney, we inactivate the genes encoding the pro-apoptotic factors BAK and BAX. In a wild-type background, the loss of <em>Bak</em> and <em>Bax</em> abrogates normal cell death and has minimal effect on renal development. However, in <em>Fgf8</em> mutants, the combined loss of <em>Bak</em> and <em>Bax</em> rescues aberrant cell death in the kidneys and restores some measure of kidney development: 1) the nephron progenitor population is greatly increased; 2) some glomeruli form, which are rarely observed in <em>Fgf8</em> mutants; and 3) kidney size is rescued by about 50% at E18.5. The development of functional nephrons, however, is not rescued. Thus, FGF8 signaling is required for nephron progenitor survival by regulating BAK/BAX and for subsequent steps involving, as yet, undefined roles in kidney development.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9486845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid signaling in mouse retina endothelial cells is required for early angiogenic growth","authors":"Christina N. Como ,&nbsp;Cesar Cervantes ,&nbsp;Brad Pawlikowski ,&nbsp;Julie Siegenthaler","doi":"10.1016/j.diff.2022.12.002","DOIUrl":"10.1016/j.diff.2022.12.002","url":null,"abstract":"<div><p>The development of the retinal vasculature is essential to maintain health of the tissue, but the developmental mechanisms are not completely understood. The aim of this study was to investigate the cell-autonomous role of retinoic acid signaling in endothelial cells during retina vascular development. Using a temporal and cell-specific mouse model to disrupt retinoic acid signaling in endothelial cells in the postnatal retina (<em>Pdgfb</em>^{<em>icre/+</em>} <em>dnRAR403</em>^{<em>fl/fl</em>} mutants), we discovered that angiogenesis in the retina is significantly decreased with a reduction in retina vascularization, endothelial tip cell number and filipodia, and endothelial ‘crowding’ of stalk cells. Interestingly, by P15, the vasculature can overcome the early angiogenic defect and fully vascularized the retina. At P60, the vasculature is intact with no evidence of retina cell death or altered blood retinal barrier integrity. Further, we identified that the angiogenic defect seen in mutants at P6 correlates with decreased <em>Vegfr3</em> expression in endothelial cells. Collectively, our work identified a previously unappreciated function for endothelial retinoic acid signaling in early retinal angiogenesis.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9486849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T, NK, then macrophages: Recent advances and challenges in adaptive immunotherapy from human pluripotent stem cells","authors":"Su Hang ,&nbsp;Nan Wang ,&nbsp;Ryohichi Sugimura","doi":"10.1016/j.diff.2023.01.001","DOIUrl":"10.1016/j.diff.2023.01.001","url":null,"abstract":"<div><p>Adaptive cellular immunotherapy, especially chimeric antigen receptor-T (CAR-T) cell therapy, has advanced the treatment of hematological malignancy. However, major limitations still remain in the source of cells comes from the patients themselves. The use of human pluripotent stem cells to differentiate into immune cells, such as T cells, NK cells, and macrophages, then arm with chimeric antigen receptor (CAR) to enhance tumor killing has gained major attention. It is expected to solve the low number of immune cells recovery from patients, long waiting periods, and ethical issues(reprogramming somatic cells to produce induced pluripotent stem cells (iPS cells) avoids the ethical issues unique to embryonic stem cells (<span>Lo and Parham, 2009</span>). However, there are still major challenges to be further solved. This review summarizes the progress, challenges, and future direction in human pluripotent stem cell-based immunotherapy.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9487938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facile methods for reusing laboratory plastic in developmental biology experiments","authors":"Maggie Clancy,&nbsp;Isabel S. Wade,&nbsp;John J. Young","doi":"10.1016/j.diff.2022.11.001","DOIUrl":"10.1016/j.diff.2022.11.001","url":null,"abstract":"<div><p>Plastic pollution negatively affects ecosystems and human health globally, with single-use plastic representing the majority of marine litter in some areas. Life science laboratories prefer pristine conditions for experimental reliability and therefore make use of factory standardized single-use plastic products. This contributes to overall plastic waste in the United States and globally. Here, we investigate the potential of reusing plastic culture dishes and subsequently propose methods to mitigate single-use plastic waste in developmental biology research laboratories. We tested the efficacy of bleach and ethyl alcohol in sterilizing used dishes. We then tested the feasibility of washing and reusing plastic to culture <em>Xenopus laevis</em> embryos subjected to various manipulations. Cleaning and reusing laboratory plastic did not affect the development or survival of <em>X. laevis</em>, indicating that these cleaning methods do not adversely affect experimental outcome and can be used to sterilize plastic before reuse or recycling. Lastly, we performed a survey of various life science laboratories to estimate both waste reduction and savings associated with recycling single-use plastics. Standardization of these procedures would allow research laboratories to benefit economically while practicing environmentally conscious consumption.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9111723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuberin levels during cellular differentiation in brain development","authors":"Elizabeth Fidalgo da Silva,&nbsp;Bashaer Abu Khatir ,&nbsp;Christopher Drouillard ,&nbsp;Isabelle Hinch ,&nbsp;Gordon Omar Davis,&nbsp;Mariam Sameem,&nbsp;Rutu Patel,&nbsp;Jackie Fong,&nbsp;Dorota Lubanska,&nbsp;Lisa A. Porter","doi":"10.1016/j.diff.2022.12.004","DOIUrl":"10.1016/j.diff.2022.12.004","url":null,"abstract":"<div><p>Tuberin is a member of a large protein complex, Tuberous Sclerosis Complex (TSC), and acts as a sensor for nutrient status regulating protein synthesis and cell cycle progression. Mutations in the Tuberin gene, <em>TSC2</em>, permits the formation of tumors that can lead to developmental defects in many organ systems, including the central nervous system. Tuberin is expressed in the brain throughout development and levels of Tuberin have been found to decrease during neuronal differentiation in cell lines <em>in vitro.</em> Our current work investigates the levels of Tuberin at two stages of embryonic development <em>in vivo</em>, and we study the mRNA and protein levels during a time course using immortalized cell lines <em>in vitro</em>. Our results show that total Tuberin levels are tightly regulated through developmental stages in the embryonic brain. At a cell biology level, we show that Tuberin levels are higher when cells are cultured as neurospheres, and knockdown of Tuberin results in a reduction in the number of neurospheres. This functional data supports the hypothesis that Tuberin is an important regulator of stemness and the reduction of Tuberin levels might support functional differentiation in the central nervous system. Understanding how Tuberin expression is regulated throughout neural development is essential to fully comprehend the role of this protein in several developmental and neural pathologies.</p></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9471048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}