Novel Insights into the Molecular Mechanisms Governing Embryonic Epicardium Formation.

The embryonic epicardium originates from the proepicardium, an extracardiac primordium constituted by a cluster of mesothelial cells. In early embryos, the embryonic epicardium is characterized by a squamous cell epithelium resting on the myocardium surface. Subsequently, it invades the subepicardial space and thereafter the embryonic myocardium by means of an epithelial-mesenchymal transition. Within the myocardium, epicardial-derived cells present multilineage potential, later differentiating into smooth muscle cells and contributing both to coronary vasculature and cardiac fibroblasts in the mature heart. Over the last decades, we have progressively increased our understanding of those cellular and molecular mechanisms driving proepicardial/embryonic epicardium formation. This study provides a state-of-the-art review of the transcriptional and emerging post-transcriptional mechanisms involved in the formation and differentiation of the embryonic epicardium.

Cardiomyocyte-Specific Wt1 Is Involved in Cardiac Metabolism and Response to Damage.

The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHCMerCreMer mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.

Pegivirus Detection in Cerebrospinal Fluid from Patients with Central Nervous System Infections of Unknown Etiology in Brazil by Viral Metagenomics.

Metagenomic next-generation sequencing (mNGS) methodology serves as an excellent supplement in cases where diagnosis is challenging to establish through conventional laboratory tests, and its usage is increasingly prevalent. Examining the causes of infectious diseases in the central nervous system (CNS) is vital for understanding their spread, managing outbreaks, and effective patient care. In a study conducted in the state of São Paulo, Brazil, cerebrospinal fluid (CSF) samples from 500 patients with CNS diseases of indeterminate etiology, collected between 2017 and 2021, were analyzed. Employing a mNGS approach, we obtained the complete coding sequence of Pegivirus hominis (HPgV) genotype 2 in a sample from a patient with encephalitis (named IAL-425/BRA/SP/2019); no other pathogen was detected. Subsequently, to determine the extent of this virus's presence, both polymerase chain reaction (PCR) and/or real-time PCR assays were utilized on the entire collection. The presence of the virus was identified in 4.0% of the samples analyzed. This research constitutes the first report of HPgV detection in CSF samples in South America. Analysis of the IAL-425 genome (9107 nt) revealed a 90% nucleotide identity with HPgV strains from various countries. Evolutionary analyses suggest that HPgV is both endemic and extensively distributed. The direct involvement of HPgV in CNS infections in these patients remains uncertain.

Hand, foot, and mouth disease outbreak by Coxsackievirus A6 during COVID-19 pandemic in 2021, São Paulo, Brazil.

INTRODUCTION: Hand, foot, and mouth disease (HFMD) is an acute febrile illness characterized by fever; sore throat; and vesicular eruptions on the hands, feet, and oral mucosa. Outbreaks of HFMD in children aged <5 years have been reported worldwide and the major causative agents are Coxsackievirus (CV)A16, enterovirus (EV)-A71 and recently CVA6. AIM AND METHODS: The aim of this study was to investigated a large outbreak of Hand, foot, and mouth disease during COVID-19 pandemic in 2021 from clinical samples of 315 suspected cases, in São Paulo State, Brazil. Diagnostic evaluation was performed by RT-qPCR, culture cell isolation and serological neutralization assay. EV-positive were genotyped by partial VP1 genome sequencing. RESULTS: One hundred and forty-nine cases analyzed were positive for enterovirus (47.3%; n = 149/315) by neutralizing test (n = 10 patients) and RT-qPCR (n = 139 patients), and identified as CVA6 sub-lineage D3 by analysis of VP1 partial sequences. CONCLUSIONS: This finding indicated the reemergence of CVA6 in HFMD, soon after the gradual easing of non-pharmaceutical interventions during-pandemic COVID-19 and the relevance of continued surveillance of circulating enterovirus types in the post-COVID pandemic era.

GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells.

In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl4-treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.

Deletion of the Wilms' Tumor Suppressor Gene in the Cardiac Troponin-T Lineage Reveals Novel Functions of WT1 in Heart Development.

Expression of Wilms' tumor suppressor transcription factor (WT1) in the embryonic epicardium is essential for cardiac development, but its myocardial expression is little known. We have found that WT1 is expressed at low levels in 20-25% of the embryonic cardiomyocytes. Conditional ablation of WT1 using a cardiac troponin T driver (Tnnt2 Cre ) caused abnormal sinus venosus and atrium development, lack of pectinate muscles, thin ventricular myocardium and, in some cases, interventricular septum and cardiac wall defects, ventricular diverticula and aneurisms. Coronary development was normal and there was not embryonic lethality, although survival of adult mutant mice was reduced probably due to perinatal mortality. Adult mutant mice showed electrocardiographic anomalies, including increased RR and QRS intervals, and decreased PR intervals. RNASeq analysis identified differential expression of 137 genes in the E13.5 mutant heart as compared to controls. GO functional enrichment analysis suggested that both calcium ion regulation and modulation of potassium channels are deeply altered in the mutant myocardium. In summary, together with its essential function in the embryonic epicardium, myocardial WT1 expression is also required for normal cardiac development.

Surveillance and molecular characterization of human sapovirus in patients with acute gastroenteritis in Brazil, 2010 to 2017.

BACKGROUND: Human sapoviruses (HuSaV) are associated with acute gastroenteritis (AGE), causing sporadic cases and outbreaks in patients worldwide. In Brazil, however, there are few reports describing the prevalence of HuSaV in patients with AGE. OBJECTIVE: Describing the diversity of HuSaV in Brazil by detecting and molecularly characterizing HuSaV among patients with AGE during an 8-year period (2010-2017). STUDY DESIGN: A total of 3974 stool samples, testing negative for rotavirus (RVA), norovirus (NoV) and human adenovirus (HAdV), were selected and screened for the presence of HuSaV. Nested RT-PCR were performed for a partial region of VP1, sequenced and genetic analyzed for genotyping the positive samples. RESULTS: In the current study, the HuSaV prevalence was determined to be 3.7% (149/3974). A higher prevalence, 5.7% (118/2074), was observed in children under 2 years of age. During the surveillance period, 13 outbreaks were detected: 12 outbreaks in children under 3 years old and one outbreak in adults. Among the 149 HuSaV positive cases, 106 samples (71%) were successfully sequenced. The most prevalent genotype found was GI.1 (44.3%), followed by GI.2 (21.7%), GI.3 (3.8%), GI.6 (2.8%), GII.1 (5.7%), GII.2 (8.5%), GII.3 (2.8%), GII.4 (2.8%), GII.5 (5.7%) and GIV.1 (1.9%). Two GIV.1 strains characterized in this study are, to date, the only strains of this genotype reported in Brazil. CONCLUSIONS: The present study elucidated the circulation of HuSaV in Brazil and highlight that HuSaV has not assumed an epidemiological importance in the country after the introduction of the RVA vaccine.

The Insulin-like Growth Factor Signalling Pathway in Cardiac Development and Regeneration.

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart.

Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background.

Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet ß cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against ß-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.

Embryonic circulating endothelial progenitor cells.

The development of vascular system in vertebrates has been traditionally explained by early vasculogenic assembly of angioblasts followed by angiogenic outgrowth of pre-existing vessels. The discovery of adult endothelial progenitor cells (Asahara et al. in Science 275(5302):964-967, 1997) challenged this view, since postnatal vascular growth could be accomplished by recruitment of circulating cells with the ability to differentiate into endothelial cells. However, the existence of embryonic circulating endothelial progenitor cells and their actual contribution to vascular development is far less known. We review in this paper the literature concerning the features, origin and physiological functions of embryonic and foetal circulating endothelial progenitors. Our review includes the early (E7.5) progenitors isolated from yolk sac, the hematovascular progenitors identified in the foetal liver, the yolk sac-derived erythro-myeloid progenitors, circulating hematopoietic cells from the G2-GATA4 lineage and the endothelial colony-forming cells isolated from the placenta and umbilical cord blood. We highlight the need of further characterization of these populations and the relationships between them.

Distribution of species enterovirus B in patients with central nervous system infections in São Paulo State, Brazil.

Enteroviruses (EV) are most common cause of central nervous system (CNS) infection, mainly aseptic meningitis. In Brazil, data available concerning the distribution of EV types are scarce. The aim of this study was to describe of types EV in patients with infection of the CNS in São Paulo State. This retrospective study was conducted in clinical samples collected from patients with infections of the CNS from 2004 to 2014. We investigated the presence of EV by virus isolation in cell culture. The samples that showed cytopathic effect in the cell culture were submitted by indirect immunofluorescence assay, reverse transcription polymerase chain reaction and VP1 partial sequencing to identification of EV isolated. A total of 176 EV isolated in cell culture was detected and typed in 14.5% (n = 176/1215) of clinical samples analyzed; corresponding to 71.0% of AM, and 19.3% of encephalitis and meningoencephalitis. Echoviruses (E) were isolated most frequently, with 155 strains (88.1%), Coxsackievirus B (CV-B), with 20 cases (11.4%), CV-A, with 01 case (0.6%). E-6 was the most commonly identified followed in decreasing order by E-30; E-18; CV-B5; E-4; E-11; CV-B2 and E-9; E-7; CV-A9, CV-B1, CV-B3, CV-B4, E-13, E-14, and E-21. EV detected were classified as belonging to the species enterovirus B. EV were detected in all the period of the year with the highest rate in the spring and summer months. Data obtained in this study contribute to the knowledge about EV circulation implicated in CNS infections over a 11-year period in São Paulo State, Brazil.

Contribution of a GATA4-Expressing Hematopoietic Progenitor Lineage to the Adult Mouse Endothelium.

Different sources have been claimed for the embryonic origin of the coronary endothelium. Recently, the potential of circulating cells as progenitors of the cardiac endothelium has also been suggested. In a previous study we have shown that circulating progenitors are recruited by the embryonic endocardium and incorporated into the coronary vessels. These progenitors derive from a mesodermal lineage characterized by the expression of Gata4 under control of the enhancer G2. Herein, we aim to trace this specific lineage throughout postnatal stages. We have found that more than 50% of the adult cardiac endothelium derives from the G2-GATA4 lineage. This percentage increases from embryos to adults probably due to differential proliferation and postnatal recruitment of circulating endothelial progenitors. In fact, injection of fetal liver or placental cells in the blood stream of neonates leads to incorporation of G2-GATA4 lineage cells to the coronary endothelium. On the other hand, labeling of the hematopoietic lineage by the stage E7.5 also resulted in positive coronary endothelial cells from both, embryos and adults. Our results suggest that early hematopoietic progenitors recruited by the embryonic ventricular endocardium can become the predominant source of definitive endothelium during the vascularization of the heart.

Epicardial cell lineages and the origin of the coronary endothelium.

The embryonic epicardium generates a population of epicardial-derived mesenchymal cells (EPDC) whose contribution to the coronary endothelium is minor or, according to some reports, negligible. We have compared four murine cell-tracing models related to the EPDC in order to elucidate this contribution. Cre recombinase was expressed under control of the promoters of the Wilms' tumor suppressor (Wt1), the cardiac troponin (cTnT), and the GATA5 genes, activating expression of the R26REYFP reporter. We have also used the G2 enhancer of the GATA4 gene as a driver due to its activation in the proepicardium. Recombination was found in most of the epicardium/EPDC in all cases. The contribution of these lineages to the cardiac endothelium was analyzed using confocal microscopy and flow cytometry. G2-GATA4 lineage cells are the most frequent in the endothelium, probably due to the recruitment of circulating endothelial progenitors. The contribution of the WT1 cell lineage increases along gestation due to further endothelial expression of WT1. GATA5 and cTnT lineages represent 4% of the cardiac endothelial cells throughout the gestation, probably standing for the actual EPDC contribution to the coronary endothelium. These results suggest caution when using a sole cell-tracing model to study the fate of the EPDC.

Retinoids in Stellate Cells: Development, Repair, and Regeneration.

Stellate cells, either hepatic (HSCs) or pancreatic (PSCs), are a type of interstitial cells characterized by their ability to store retinoids in lipid vesicles. In pathological conditions both HSCs and PSCs lose their retinoid content and transform into fibroblast-like cells, contributing to the fibrogenic response. HSCs also participate in other functions including vasoregulation, drug detoxification, immunotolerance, and maintenance of the hepatocyte population. PSCs maintain pancreatic tissue architecture and regulate pancreatic exocrine function. Recently, PSCs have attracted the attention of researchers due to their interactions with pancreatic ductal adenocarcinoma cells. PSCs promote tumour growth and angiogenesis, and their fibrotic activity increases the resistance of pancreatic cancer to chemotherapy and radiation. We are reviewing the current literature concerning the role played by retinoids in the physiology and pathophysiology of the stellate cells, paying attention to their developmental aspects as well as the function of stellate cells in tissue repair and organ regeneration.

First Detection of DS-1-like G1P[8] Double-gene Reassortant Rotavirus Strains on The American Continent, Brazil, 2013.

Emergence of DS-1-like-G1P[8] rotavirus in Asia have been recently reported. We report for the first time the detection and the whole genome phylogenetic analysis of DS-1-like-G1P[8] strains in America. From 2013 to 2017, a total of 4226 fecal samples were screened for rotavirus by ELISA, PAGE, RT-PCR and sequencing. G1P[8] represented 3.7% (30/800) of all rotavirus-positive samples. DS-1-like-G1P[8] comprised 1.6% (13/800) detected exclusively in 2013, and Wa-like-G1P[8] comprised 2.1% (17/800) detected from 2013 to 2015. Whole genome sequencing confirmed the DS-1-like backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. All genome segments of the Brazilian DS-1-like-G1P[8] strains clustered with those of Asian strains, and apart from African DS-1-like-G1P[8] strains. In addition, Brazilian DS-1-like-G1P[8] reassortants distantly clustered with DS-1-like backbone strains simultaneously circulating in the country, suggesting that the Brazilian DS-1-like-G1P[8] strains are likely imported from Asia. Two distinct NSP4 E2 genotype lineages were also identified, indicating the existence of a co-circulating pool of different DS-1-like G1P[8] strains. Surveillance systems must be developed to examine if RVA vaccines are still effective for the prevention against unusual DS-1-like-G1P[8] strains.

The Wilms' tumor suppressor gene regulates pancreas homeostasis and repair.

The Wilms' tumor suppressor gene (Wt1) encodes a zinc finger transcription factor that plays an essential role in the development of kidneys, gonads, spleen, adrenals and heart. Recent findings suggest that WT1 could also be playing physiological roles in adults. Systemic deletion of WT1 in mice provokes a severe deterioration of the exocrine pancreas, with mesothelial disruption, E-cadherin downregulation, disorganization of acinar architecture and accumulation of ascitic transudate. Despite this extensive damage, pancreatic stellate cells do not become activated and lose their canonical markers. We observed that pharmacological induction of pancreatitis in normal mice provokes de novo expression of WT1 in pancreatic stellate cells, concomitant with their activation. When pancreatitis was induced in mice after WT1 ablation, pancreatic stellate cells expressed WT1 and became activated, leading to a partial rescue of the acinar structure and the quiescent pancreatic stellate cell population after recovery from pancreatitis. We propose that WT1 modulates through the RALDH2/retinoic acid axis the restabilization of a part of the pancreatic stellate cell population and, indirectly, the repair of the pancreatic architecture, since quiescent pancreatic stellate cells are required for pancreas stability and repair. Thus, we suggest that WT1 plays novel and essential roles for the homeostasis of the adult pancreas and, through its upregulation in pancreatic stellate cells after a damage, for pancreatic regeneration. Due to the growing importance of the pancreatic stellate cells in physiological and pathophysiological conditions, these novel roles can be of translational relevance.

Mesothelial-mesenchymal transitions in embryogenesis.

Most animals develop coelomic cavities lined by an epithelial cell layer called the mesothelium. Embryonic mesothelial cells have the ability to transform into mesenchymal cells which populate many developing organs contributing to their connective and vascular tissues, and also to organ-specific cell types. Furthermore, embryonic mesothelium and mesothelial-derived cells produce essential signals for visceral morphogenesis. We review the most relevant literature about the mechanisms regulating the embryonic mesothelial-mesenchymal transition, the developmental fate of the mesothelial-derived cells and other functions of the embryonic mesothelium, such as its contribution to the establishment of left-right visceral asymmetries or its role in limb morphogenesis.

Spread of the emerging equine-like G3P[8] DS-1-like genetic backbone rotavirus strain in Brazil and identification of potential genetic variants.

In 2013, the equine-like G3P[8] DS-1-like rotavirus (RVA) strain emerged worldwide. In 2016, this strain was reported in northern Brazil. The aims of the study were to conduct a retrospective genetic investigation to identify the possible entry of these atypical strains in Brazil and to describe their distribution across a representative area of the country. From 2013 to 2017, a total of 4226 faecal samples were screened for RVA by ELISA, PAGE, RT-PCR and sequencing. G3P[8] represented 20.9 % (167/800) of all RVA-positive samples, further subdivided as equine-like G3P[8], DS-1-like (11.0 %; 88/800) and Wa-like G3P[8] (9.9 %; 79/800). Six equine-like G3P[8] DS-1-like samples were selected for whole-genome investigation, confirming the backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. During 2013-2014, Wa-like G3P[8] was predominant and no equine-like G3P[8] DS-1-like was detected. Equine-like G3P[8] DS-1-like was first identified in Paraná in March/2015, suggesting that the strain entered Brazil through the Southern region. Equine-like G3P[8] rapidly spread across the area under surveillance and displayed a marked potential to replace Wa-like G3P[8] strains. Brazilian equine-like G3P[8] DS-1-like strains clustered with contemporary equine-like G3P[8] DS-1-like detected worldwide, but exhibited a distinct NSP2 genotype (N2) compared to the previously reported Amazon equine-like G3P[8] DS-1-like strain (N1). Two distinct NSP4 E2 genotype lineages were also identified. Taken together, these data suggest that different variants of equine-like G3P[8] DS-1-like strains might have been introduced into the country at distinct time points, and co-circulated in the period 2015-2017. The global emergence of equine-like G3P[8] DS-1-like strains, predominantly in countries using the Rotarix vaccine, raises the question of whether vaccines may be inducing selective pressures on zoonotic strains.

Role of the Wilms' tumor suppressor gene Wt1 in pancreatic development.

The Wilms tumor suppressor gene (Wt1) encodes a transcription factor involved in the development of a number of organs, but the role played by Wt1 in pancreatic development is unknown. The pancreas contains a population of pancreatic stellate cells (PSC) very important for pancreatic physiology. We described elsewhere that hepatic stellate cells originate from the WT1-expressing liver mesothelium. Thus, we checked if the origin of PSCs was similar. WT1 expression is restricted to the pancreatic mesothelium. Between embryonic day (E) 10.5 and E15.5, this mesothelium gives rise to mesenchymal cells that contribute to a major part of the PSC and other cell types including endothelial cells. Most WT1 systemic mutants show abnormal localization of the dorsal pancreas within the mesentery and intestinal malrotation by E14.0. Embryos with conditional deletion of WT1 between E9.5 and E12.5 showed normal dorsal pancreatic bud and intestine, but the number of acini in the ventral bud was reduced approximately 30% by E16.5. Proliferation of acinar cells was reduced in WT1 systemic mutants, but pancreatic differentiation was not impaired. Thus, mesothelial-derived cells constitute an important subpopulation of pancreatic mesodermal cells. WT1 expression is not essential for pancreas development, although it influences intestinal rotation and correct localization of the dorsal pancreas within the mesogastrium. Developmental Dynamics 247:924-933, 2018. © 2018 Wiley Periodicals, Inc.

Comparative developmental biology of the cardiac inflow tract.

The vertebrate heart receives the blood through the cardiac inflow tract. This area has experienced profound changes along the evolution of vertebrates; changes that have a reflection in the cardiac ontogeny. The development of the inflow tract involves dynamic changes due to the progressive addition of tissue derived from the secondary heart field. The inflow tract is the site where oxygenated blood coming from lungs is received separately from the systemic return, where the cardiac pacemaker is established and where the proepicardium develops. Differential cell migration towards the inflow tract breaks the symmetry of the primary heart tube and determines the direction of the cardiac looping. In air-breathing vertebrates, an inflow tract reorganization is essential to keep separate blood flows from systemic and pulmonary returns. Finally, the sinus venosus endocardium has recently been recognized as playing a role in the constitution of the coronary vasculature. Due to this developmental complexity, congenital anomalies of the inflow tract can cause severe cardiac diseases. We aimed to review the recent literature on the cellular and molecular mechanisms that regulate the morphogenesis of the cardiac inflow tract, together with comparative and evolutionary details, thus providing a basis for a better understanding of these mechanisms.