Mark Hill (talk) 12:23, 16 June 2019 (AEST) Added this new page to capture updated references added throughout the site in the "Some Recent Findings". Entries are listed alphabetically by topic page, note that not all new references may be added to this current list. (More? New)
- BMP controls dorsoventral and neural patterning in indirect-developing hemichordates providing insight into a possible origin of chordates "A defining feature of chordates is the unique presence of a dorsal hollow neural tube that forms by internalization of the ectodermal neural plate specified via inhibition of BMP signaling during gastrulation. While BMP controls dorsoventral (DV) patterning across diverse bilaterians, the BMP-active side is ventral in chordates and dorsal in many other bilaterians. How this phylum-specific DV inversion occurs and whether it is coupled to the emergence of the dorsal neural plate are unknown. Here we explore these questions by investigating an indirect-developing enteropneust from the hemichordate phylum, which together with echinoderms form a sister group of the chordates. We found that in the hemichordate larva, BMP signaling is required for DV patterning and is sufficient to repress neurogenesis. We also found that transient overactivation of BMP signaling during gastrulation concomitantly blocked mouth formation and centralized the nervous system to the ventral ectoderm in both hemichordate and sea urchin larvae. Moreover, this mouthless, neurogenic ventral ectoderm displayed a medial-to-lateral organization similar to that of the chordate neural plate. Thus, indirect-developing deuterostomes use BMP signaling in DV and neural patterning, and an elevated BMP level during gastrulation drives pronounced morphological changes reminiscent of a DV inversion. These findings provide a mechanistic basis to support the hypothesis that an inverse chordate body plan emerged from an indirect-developing ancestor by tinkering with BMP signaling."
- Fetal Growth Restriction Alters Cerebellar Development in Fetal and Neonatal sheep "Fetal growth restriction (FGR) complicates 5-10% of pregnancies and is associated with increased risks of perinatal morbidity and mortality. The development of cerebellar neuropathology in utero, in response to chronic fetal hypoxia, and over the period of high risk for preterm birth, has not been previously studied. ... FGR lambs demonstrated neuropathology within the cerebellum after birth, with a significant, ~18% decrease in the number of granule cell bodies (NeuN+ immunoreactivity) within the internal granular layer (IGL) and an ~80% reduction in neuronal extension and branching (MAP+ immunoreactivity) within the molecular layer (ML). Oxidative stress (8-OHdG+ immunoreactivity) was significantly higher in FGR lambs within the ML and the white matter (WM) compared to control lambs. The structural integrity of neurons was already aberrant in the FGR cerebellum at 115 d GA, and by 124 d GA, inflammatory cells (Iba-1+ immunoreactivity) were significantly upregulated and the blood-brain barrier (BBB) was compromised (Pearls, albumin, and GFAP+ immunoreactivity). We confirm that cerebellar injuries develop antenatally in FGR, and therefore, interventions to prevent long-term motor and coordination deficits should be implemented either antenatally or perinatally, thereby targeting neuroinflammatory and oxidative stress pathways."
- Review - A mechanism for the effect of endocrine disrupting chemicals on placentation "Numerous recent studies have shown that endocrine disrupting chemicals (EDCs) in the body of pregnant women can pass through the placenta and be exposed to the fetus, leading to fetal development and cognitive impairment. Placentation through invasion of trophoblast cells and vascular remodeling is essential to maintaining maternal and fetal health throughout the pregnancy. Abnormal placentation can lead to pregnancy disorders such as preeclampsia (PE) and intrauterine growth retardation (IUGR). However, many studies have not been conducted on whether EDCs can inhibit the development and function of the placenta. Isolating placental tissues to analyze the effect of EDCs on placentation has several limitations. In this review, we discussed the types of EDCs that can pass through the placental barrier and accumulate in the placenta with relative outcome. EDCs can be released from a variety of products including plasticizers, pesticides, and retardant. We also discussed the development and dysfunction of the placenta when EDCs were treated on trophoblast cells or pregnant rodent models. The effects of EDCs on the placenta of livestock are also discussed, together with the molecular mechanism of EDCs acting in trophoblast cells. We describe how EDCs cross the membrane of trophoblasts to regulate signaling pathways, causing genetic and epigenetic changes that lead to changes in cell viability and invasiveness. Further studies on the effects of EDCs on placenta may draw attention to the correct use of products containing EDCs during pregnancy."
- Toxicokinetics of bisphenol A, bisphenol S, and bisphenol F in a pregnancy sheep model "Bisphenol A (BPA), S (BPS), and F (BPF) are among the most abundant bisphenols detected in humans, yet pregnancy toxicokinetics for BPS or BPF remain unknown. Because gestational BPS can disrupt placental function and result in reproductive and metabolic disorders in the progeny, the aim of the study was to investigate BPS and BPF toxicokinetics during pregnancy using an in vivo approach. ... We observed significant differences in half-life, maximum concentration, and total body clearance in maternal circulation among bisphenols. Longer half-lives were observed in fetal vs. maternal circulation for all bisphenols. Fetal toxicokinetics differed among bisphenols with BPS having the longest fetal half-life. All bisphenols reached basal levels at 48 h in maternal plasma, but were still detectable in amniotic fluid, fetal urine, and fetal plasma at 72 h. In this first pregnancy toxicokinetic study of BPS and BPF we have demonstrated maternal and fetal toxicokinetic differences among all three bisphenols. Higher BPS persistence in the fetal compartment warrants studies into progeny adverse outcomes following gestational exposure. Additionally, toxicokinetic differences among bisphenols call for a more careful approach when extrapolating kinetic information from one bisphenol chemical to another."
- SLC9A3 Affects Vas Deferens Development and Associates with Taiwanese Congenital Bilateral Absence of the Vas Deferens "The pathophysiology of Taiwanese congenital bilateral absence of the vas deferens (CBAVD) is different from that in Caucasians. In particular, major cystic fibrosis transmembrane conductance regulator (CFTR) mutations and cystic fibrosis are absent in the former. DISCUSSION: Our findings build upon previous data associated with CBAVD pathogenesis. Here, we now report for the first time an association between CBAVD and loss of SLC9A3 and propose that specific defects in the reproductive duct due to SLC9A3 variants drive CBAVD development. CONCLUSION: The data implicate loss of SLC9A3 as a basis of Taiwanese CBAVD and highlight SLC9A3 function in reproduction." OMIM - SLC9A3
fetal growth restriction
- Outcomes in patients with early-onset fetal growth restriction without fetal or genetic anomalies "Early-onset fetal growth restriction is associated with poor pregnancy outcomes, but frequently is due to fetal structural or chromosomal abnormalities. The objective of this study was to determine outcomes in patients with early-onset fetal growth restriction without diagnosed fetal or genetic anomalies and to identify additional risk factors for poor outcomes in these patients. This was retrospective cohort study of singleton pregnancies in women with early-onset growth restriction defined as a sonographic estimated fetal weight <10% diagnosed between 16-28 weeks' gestation. We excluded all women with a fetal structural or chromosomal abnormality diagnosed prenatally. Data on pregnancy characteristics and outcomes were collected and analyzed for estimated fetal weight <10% and ≤5%. A nested case-control study within the cohort of patients with ongoing pregnancies was then performed to identify risk factors associated with poor pregnancy outcome using chi-squared test. One hundred forty-two patients were identified who met inclusion and exclusion criteria and 20 patients were found to have fetal structural or chromosomal abnormalities. In the remaining 122 patients, the incidence of intrauterine fetal demise was 5.7% and there were high rates of preterm birth <37 weeks (20%), birth weight <10% (59.3%), and gestational hypertension (14.1%). Later gestational age at diagnosis and the presence of echogenic bowel and abnormal initial umbilical artery Dopplers were associated with poor pregnancy outcome (22.56 versus 20.86 weeks, p = .046), (17.4 versus 2.2%, OR 9.68, 95%CI 1.65-56.73), and (35.3 versus 0%, OR 4.46, 95%CI 2.65-7.50) respectively. Patients with early-onset fetal growth restriction with no fetal structural or genetic abnormality have a high risk of poor pregnancy outcomes. Gestational age at diagnosis and certain ultrasound findings are associated with poor pregnancy outcome."
- Bmp4 is an essential growth factor for the initiation of genital tubercle (GT) outgrowth "The external genitalia are appendage organs outgrowing from the posterior body trunk. Murine genital tubercle (GT), anlage of external genitalia, initiates its outgrowth from embryonic day (E) E10.5 as a bud structure. Several growth factors such as fibroblast growth factor (FGF), Wnt and Sonic hedgehog (Shh) are essential for the GT outgrowth. However, the mechanisms of initiation of GT outgrowth are poorly understood. We previously identified bone morphogenetic protein (Bmp) signaling as a negative regulator for GT outgrowth. We show here novel aspects of Bmp4 functions for GT outgrowth. We identified the Bmp4 was already expressed in cloaca region at E9.5, before GT outgrowth. To analyze the function of Bmp4 at early stage for the initiation of GT outgrowth, we utilized the Hoxa3-Cre driver and Bmp4 flox/flox mouse lines. Hoxa3 Cre/+ ; Bmp4 flox/flox mutant mice showed the hypoplasia of GT with reduced expression of outgrowth promoting genes such as Wnt5a, Hoxd13 and p63, whereas Shh expression was not affected. Formation of distal urethral epithelium (DUE) marked by the Fgf8 expression is essential for controlling mesenchymal genes expression in GT and subsequent its outgrowth. Furthermore, Fgf8 expression was dramatically reduced in such mutant mice indicating the defective DUE formation. Hence, current results indicate that Bmp4 is an essential growth factor for the initiation of GT outgrowth independent of Shh signaling. Thus, Bmp4 positively regulates for the formation of DUE. The current study provides new insights into the function of Bmp signaling at early stage for the initiation of GT outgrowth." BMP
- Development of the Basal Hypothalamus through Anisotropic Growth "The adult hypothalamus is subdivided into distinct domains: pre-optic, anterior, tuberal and mammillary. Each domain harbours an array of neurons that act together to regulate homeostasis. The embryonic origins and development of hypothalamic neurons, however, remains enigmatic. Here we summarise recent studies in model organisms that challenge current views of hypothalamic development, which traditionally have attempted to map adult domains to correspondingly-located embryonic domains that expand isotropically. Instead, new studies indicate that hypothalamic neurons arise from progenitor cells that undergo anisotropic growth in different dimensions. Here we describe how a multipotent Shh/ Fgf10-expressing progenitor population gives rise to progenitors that grow anisotropically, expanding to a greater extent than other progenitors and giving rise to cells throughout the basal hypothalamus. Further, Shh/Fgf10+ive -derived progenitors grow sequentially in different directions from the multipotent Shh/ Fgf10 population: first, a subset displaced rostrally give rise to anterior-ventral/tuberal neuronal progenitors, then a subset displaced caudally give rise to mammillary neuronal progenitors; finally, a subset(s) displaced ventrally give rise to tuberal infundibular glial progenitors. As this occurs, stable populations of Shh+ive and Fgf10+ive progenitors form. We describe current understanding of the mechanisms that induce Shh/Fgf10+ive progenitors, and begin to direct their differentiation to anterior-ventral/tuberal neuronal progenitors, mammillary neuronal progenitors and tuberal infundibular progenitors. Together these studies suggest a new model for hypothalamic development that we term the Anisotropic growth model. We discuss the implications of the model for understanding the origins of adult hypothalamic neurons."
- A human liver cell atlas reveals heterogeneity and epithelial progenitors "The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers."
- The contributions of mesoderm-derived cells in liver development "The liver is an indispensable organ for metabolism and drug detoxification. The liver consists of endoderm-derived hepatobiliary lineages and various mesoderm-derived cells, and interacts with the surrounding tissues and organs through the ventral mesentery. Liver development, from hepatic specification to liver maturation, requires close interactions with mesoderm-derived cells, such as mesothelial cells, hepatic stellate cells, mesenchymal cells, liver sinusoidal endothelial cells and hematopoietic cells. These cells affect liver development through precise signaling events and even direct physical contact. Through the use of new techniques, emerging studies have recently led to a deeper understanding of liver development and its related mechanisms, especially the roles of mesodermal cells in liver development. Based on these developments, the current protocols for in vitro hepatocyte-like cell induction and liver-like tissue construction have been optimized and are of great importance for the treatment of liver diseases. Here, we review the roles of mesoderm-derived cells in the processes of liver development, hepatocyte-like cell induction and liver-like tissue construction."
- Molecular recording of mammalian embryogenesis "Ontogeny describes the emergence of complex multicellular organisms from single totipotent cells. This field is particularly challenging in mammals, owing to the indeterminate relationship between self-renewal and differentiation, variation in progenitor field sizes, and internal gestation in these animals. Here we present a flexible, high-information, multi-channel molecular recorder with a single-cell readout and apply it as an evolving lineage tracer to assemble mouse cell-fate maps from fertilization through gastrulation. By combining lineage information with single-cell RNA sequencing profiles, we recapitulate canonical developmental relationships between different tissue types and reveal the nearly complete transcriptional convergence of endodermal cells of extra-embryonic and embryonic origins. Finally, we apply our cell-fate maps to estimate the number of embryonic progenitor cells and their degree of asymmetric partitioning during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems, which will facilitate the construction of a quantitative framework for understanding developmental processes."
- Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2 "Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). ... Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB." OMIM - SLIT2 | OMIM - ROBO1
- XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage "The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry- mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry- females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry- PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry- oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as "Swyer syndrome," in which patients with an XY karyotype present as typical females and are infertile."
- Venous Collateral Pathways in Superior Thoracic Inlet Obstruction: A Systematic Analysis of Anatomy, Embryology, and Resulting Patterns "For this study, we reviewed 56 standard-of-care CT examinations over a timespan of 2 years from patients with superior thoracic inlet venous obstruction and identified eight thoracic collateral pathways for venous blood return to the right heart. We evaluated each pathway individually from an anatomic and a pathophysiologic perspective for a better understanding of how such pathways form and what patterns can be expected. ... Recognizing imaging findings associated with venous collateral pathways may prevent misdiagnosis or unnecessary follow-up examinations. Furthermore, knowledge of these collateral pathways and an understanding of the underlying cause can support interventional radiologists and vascular surgeons in planning interventional procedures and revascularization procedures."
- The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist "The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes Xist and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other's TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes."
- Pleomorphic Adenoma Gene 1 Is Needed For Timely Zygotic Genome Activation and Early Embryo Development "Pleomorphic adenoma gene 1 (PLAG1) is a transcription factor involved in cancer and growth. We discovered a de novo DNA motif containing a PLAG1 binding site in the promoters of genes activated during zygotic genome activation (ZGA) in human embryos. This motif was located within an Alu element in a region that was conserved in the murine B1 element. We show that maternally provided Plag1 is needed for timely mouse preimplantation embryo development. Heterozygous mouse embryos lacking maternal Plag1 showed disrupted regulation of 1,089 genes, spent significantly longer time in the 2-cell stage, and started expressing Plag1 ectopically from the paternal allele. The de novo PLAG1 motif was enriched in the promoters of the genes whose activation was delayed in the absence of Plag1. Further, these mouse genes showed a significant overlap with genes upregulated during human ZGA that also contain the motif. By gene ontology, the mouse and human ZGA genes with de novo PLAG1 motifs were involved in ribosome biogenesis and protein synthesis. Collectively, our data suggest that PLAG1 affects embryo development in mice and humans through a conserved DNA motif within Alu/B1 elements located in the promoters of a subset of ZGA genes."
- ↑ Su YH, Chen YC, Ting HC, Fan TP, Lin CY, Wang KT & Yu JK. (2019). BMP controls dorsoventral and neural patterning in indirect-developing hemichordates providing insight into a possible origin of chordates. Proc. Natl. Acad. Sci. U.S.A. , , . PMID: 31189599 DOI.
- ↑ Yawno T, Sutherland AE, Pham Y, Castillo-Melendez M, Jenkin G & Miller SL. (2019). Fetal Growth Restriction Alters Cerebellar Development in Fetal and Neonatal Sheep. Front Physiol , 10, 560. PMID: 31191328 DOI.
- ↑ Yang C, Song G & Lim W. (2019). A mechanism for the effect of endocrine disrupting chemicals on placentation. Chemosphere , 231, 326-336. PMID: 31132539 DOI.
- ↑ Gingrich J, Pu Y, Ehrhardt R, Karthikraj R, Kannan K & Veiga-Lopez A. (2019). Toxicokinetics of bisphenol A, bisphenol S, and bisphenol F in a pregnancy sheep model. Chemosphere , 220, 185-194. PMID: 30583211 DOI.
- ↑ Wu YN, Chen KC, Wu CC, Lin YH & Chiang HS. (2019). SLC9A3 Affects Vas Deferens Development and Associates with Taiwanese Congenital Bilateral Absence of the Vas Deferens. Biomed Res Int , 2019, 3562719. PMID: 30956978 DOI.
- ↑ Gupta S, Naert M, Lam-Rachlin J, Monteagudo A, Rebarber A, Saltzman D & Fox NS. (2019). Outcomes in patients with early-onset fetal growth restriction without fetal or genetic anomalies. J. Matern. Fetal. Neonatal. Med. , 32, 2662-2666. PMID: 29478342 DOI.
- ↑ Kajioka D, Suzuki K, Nakada S, Matsushita S, Miyagawa S, Takeo T, Nakagata N & Yamada G. (2019). Bmp4 is an essential growth factor for the initiation of genital tubercle (GT) outgrowth. Congenit Anom (Kyoto) , , . PMID: 30714224 DOI.
- ↑ Fu T, Pearson C, Towers M & Placzek M. (2019). Development of the Basal Hypothalamus through Anisotropic Growth. J. Neuroendocrinol. , , e12727. PMID: 31050853 DOI.
- ↑ Aizarani N, Saviano A, Sagar L, Mailly S, Durand JS, Herman P, Pessaux TF, Baumert D & Grün. (2019). A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature , , . PMID: 31292543 DOI.
- ↑ Yang L, Li LC, Lamaoqiezhong X, Wang WH, Wang YC, Wang CR & Xu. (2019). The contributions of mesoderm-derived cells in liver development. Semin. Cell Dev. Biol. , 92, 63-76. PMID: 30193996 DOI.
- ↑ Chan MM, Smith ZD, Grosswendt S, Kretzmer H, Norman TM, Adamson B, Jost M, Quinn JJ, Yang D, Jones MG, Khodaverdian A, Yosef N, Meissner A & Weissman JS. (2019). Molecular recording of mammalian embryogenesis. Nature , 570, 77-82. PMID: 31086336 DOI.
- ↑ Tiensuu H, Haapalainen AM, Karjalainen MK, Pasanen A, Huusko JM, Marttila R, Ojaniemi M, Muglia LJ, Hallman M & Rämet M. (2019). Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2. PLoS Genet. , 15, e1008107. PMID: 31194736 DOI.
- ↑ Sakashita A, Wakai T, Kawabata Y, Nishimura C, Sotomaru Y, Alavattam KG, Namekawa SH & Kono T. (2019). XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage†. Biol. Reprod. , 100, 697-710. PMID: 30289439 DOI.
- ↑ Meier A & Alkadhi H. (2019). Venous Collateral Pathways in Superior Thoracic Inlet Obstruction: A Systematic Analysis of Anatomy, Embryology, and Resulting Patterns. AJR Am J Roentgenol , , 1-11. PMID: 31039029 DOI.
- ↑ van Bemmel JG, Galupa R, Gard C, Servant N, Picard C, Davies J, Szempruch AJ, Zhan Y, Żylicz JJ, Nora EP, Lameiras S, de Wit E, Gentien D, Baulande S, Giorgetti L, Guttman M, Hughes JR, Higgs DR, Gribnau J & Heard E. (2019). The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist. Nat. Genet. , 51, 1024-1034. PMID: 31133748 DOI.
- ↑ Madissoon E, Damdimopoulos A, Katayama S, Krjutškov K, Einarsdottir E, Mamia K, De Groef B, Hovatta O, Kere J & Damdimopoulou P. (2019). Pleomorphic Adenoma Gene 1 Is Needed For Timely Zygotic Genome Activation and Early Embryo Development. Sci Rep , 9, 8411. PMID: 31182756 DOI.