Wt1 is involved in pancreas development and adult pancreatic homeostasis

The embryonic mesothelium lining the visceral organs gives rise to mesenchymal cells through a localized epithelial-mesenchymal transition (EMT). This has been extensively studied in some cases, such as the heart, where the epicardium gives rise to epicardial-derived cells that contribute to the cardiac vascular and connective tissues. In other organs, such as the lungs, liver and gut, the developmental fate of the mesothelial-derived mesenchyme and their importance for visceral morphogenesis has also been demonstrated (reviewed in Ariza et al., Dev Dyn, 2016, 245:307-22). Hepatic stellate cells (HSC) are located in the perisinusoidal space of the liver. It has been described that cells derived from the liver mesothelium through an EMT contributes to the HSC population and also to the sinusoidal endothelium during development (IJpenberg et al. Dev Biol, 2007, 312: 157–170; Asahina et al., Hepatology, 2011, 53:983-95). Thus, we checked is a similar developmental origin accounts for pancreatic stellate cells (PSC), a population of pancreatic stromal cells that share many features with HSC. In normal adult pancreas, PSC are quiescent, star-shaped cells with a periacinar distribution. When activated by profibrogenic stimuli such as inflammatory cytokines or oxidative stress, PSC transform into myofibroblast-like cells. Thus, PSC are the major source of extracellular matrix in the adult pancreas, but their embryonic origin remains unknown. The Wilms’ tumor suppressor gene (Wt1) is highly expressed in the embryonic mesothelium. For this reason, we have used two lines of transgenic mice for lineage tracing of mesothelial-derived cells, systemic (Wt1Cre; R26REYFP), tamoxifen-inducible (Wt1ERT2; R26REYFP) and we have also used the inducible driver for conditional deletion of Wt1 (Wt1ERT2; Wt1 flox) in adult mice. Our results confirm that WT1 protein is only expressed in the mesothelium of the developing pancreas, allowing for reliable tracing of the mesothelial-derived cells. During the early stages of pancreas morphogenesis, its mesothelium shows the typical features of EMT. Mesothelial-derived cells, identified by constitutive YFP expression, differentiate into a major part of the PSCs and also contribute to other connective and vascular cell type, including endothelium. Thus, mesothelial-derived cells originated by EMT seem to constitute an important subpopulation of mesodermal cells during pancreas development, contributing to its morphogenesis. On the other hand, systemic deletion of Wt1 in adult mice causes a severe atrophy of the pancreas, although this factor is only expressed in the pancreatic mesothelium. In addition, we have observed that adult PSC express Wt1 in the caerulein-induced pancreatitis model. Our results suggest that: 1) normal pancreatic function is maintained by a Wt1-dependent signaling mechanism acting from the mesothelium and 2) Wt1 plays a role in PSC activation in adult mice. These observations point to a relevant function of the Wt1 gene in pancreatic development and function.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Expression of the Wilms tumor suppressor gene (Wt1) in a subpopulation of embryonic cardiomyocytes is required for cardiac development

The Wilms’ tumour gene, WT1, encodes a zinc-finger transcription factor involved in the development of several organs. WT1 is expressed during mammalian embryonic development in many tissues, including the urogenital system, spleen, spinal cord, diaphragm, coelomic epithelium and epicardium (Armstrong et al., 1993; Moore et al., 1999; Cano et al., 2016; Ariza et al., 2016; Carmona et al., 2016). Post-transcriptional modifications of the Wt1 pre-mRNA lead to the production of up to 24 different isoforms, which seem to serve distinct but overlapping cellular and developmental functions. We have checked if Wt1 is expressed by the embryonic myocardium. Using transgenic mice lines for lineage tracing (mWt1/IRES/GFPCre;ROSA26REYFP), we have detected a small population of cardiomyocytes from a Wt1-expressing cell lineage in early developmental stages (E8.5-E9.5). These cardiomyocytes were mainly located in the inflow tract, but some of them were observed in the ventricles. We confirmed Wt1 expression by RT-PCR in hearts before the attachment of proepicardial cells, when the cardiac tube is only constituted of myocardium and endocardium. We have also studied the mRNA levels of the four main isoforms of Wt1 in a reverse transcriptase-polymerase chain reaction (RT- PCR) assay. We have found differential expression of these Wt1 isoforms in the embryonic heart. Conditional deletion of Wt1 in cardiac Troponin T expressing cells caused severe damage in the developing heart, particularly muscular defects in the interventricular septum and free ventricular walls, as well as defective sinus venous formation. These embryos did not survive after birth. Likewise, conditional deletion of GATA4 in Wt1-expressing cells causes a similar phenotype in the myocardium, but also defects in the proepicardium, epicardium and subepicardial space, causing embryonic death around E11.5. Thus, we conclude that Wt1 is expressed in a subpopulation of early embryonic cardiomyocytes, and this expression seems to be essential for heart development.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Quasi-filiform Leibniz algebras of maximum length

The n-dimensional p-filiform Leibniz algebras of maximum length have already been studied with 0 p 2. For Lie algebras whose nilindex is equal to n − 2 there is only one characteristic sequence, (n − 2, 1, 1), while in Leibniz theory we obtain two possibilities: (n−2, 1, 1) and (n−2, 2). The first case (the 2-filiform case) is already known. The present paper deals with the second case, i.e., quasi-filiform non Lie Leibniz algebras of maximum length. Therefore this work completes the study of maximum length of Leibniz algebras with nilindex n − p with 0 p 2.Junta de Andalucía FQM-14

3-filiform Leibniz algebras of maximum length

This work completes the study of the solvable Leibniz algebras, more precisely, it completes the classi cation of the 3- liform Leibniz algebras of maximum length [4]. Moreover, due to the good structure of the algebras of maximum length, we also tackle some of their cohomological properties. Our main tools are the previous result of Cabezas and Pastor [3], the construction of appropriate homogeneous basis in the considered connected gradation and the computational support provided by the two programs implemented in the software Mathematica.Ministerio de Economía y Competitividad MTM2013–43687–

p-Filiform Leibniz algebras of maximum length

The descriptions (up to isomorphism) of naturally graded p-filiform Leibniz algebras and p-filiform (p 3) Leibniz algebras of maximum length are known. In this paper we study the gradation of maximum length for p-filiform Leibniz algebras. The present work aims at the classification of complex p-filiform (p 4) Leibniz algebras of maximum length

El ácido úrico se asocia con características de un síndrome de resistencia insulínica en los niños obesos en etapas perdurables

Elevated plasma uric acid levels are associated with obesity and could be an expression of insulin-resistant state. The aim of the present study was to evaluate plasma uric acid in obese and normal-weight children exclusively at prepubertal stage and its relationship with anthropometric measurements, intake, and features of the insulin resistance syndrome. A study was performed in 34 obese and 20 normal- weight prepubertal children. Nutrient intake was determined using a 72 h recall questionnaire and a consumption food frequency questionnaire. Anthropometric parameters and fasting plasma lipids, glucose, insulin, leptin, adiponectin, tumour necrosis factor (TNF-α) and uric acid were measured. Multiple regression analysis was used to identify association of anthropometric parameters, nutrient intake and insulin resistance syndrome variables (arterial blood pressure, plasma glucose, insulin, homeostasis model assessment of insulin resistance index- HOMA- triacylglycerols and, HDL-cholesterol) with uric acid. Plasma uric concentration was significantly higher in the obese group than in the control group and when adjusted by sex, age and BMI was positively associated with tricipital skinfold and insulin resistance, and negatively with adiponectin. In multiple regression analysis, BMI, HDL-cholesterol and adiponectin were independent predictors of plasma uric acid. In conclusion, elevated levels of uric acid in obese children, compared with lean subjects, at the prepubertal period, seems to be an early metabolic alteration that is associated with other features of insulin resistance syndrome.Los niveles elevados de ácido úrico plasmáticos se asocian a la obesidad y pueden ser la expresión de un estado de resistencia insulínica. El objetivo de este estudio ha sido evaluar la concentración plasmática de ácido úrico en niños obesos y normales, exclusivamente en edad prepuberal, y determinar su relación con las medidas antropométricas, la ingesta dietética y los parámetros asociados al síndrome de resistencia insulínica. El estudio se llevó a cabo en 34 niños obesos y 20 controles en edad prepuberal a los cuales se les estimó su ingesta dietética mediante el registro de un cuestionario de ingesta de alimentos de 72 h y un cuestionario de frecuencia de consumo de alimentos y se determinaron, además de los parámetros antropométricos, la glucosa, la insulina, la leptina, la adiponectina y el factor de necrosis tumoral alfa (TNF-α) plasmáticos. Se realizó un análisis de regresión múltiple para identificar la asociación entre los niveles de ácido úrico y los parámetros antropométricos, la ingesta de nutrientes y las variables clásicas relacionadas con el síndrome de resistencia insulínica (hipertensión, glucosa, insulina, índice de resistencia insulínica HOMA, triglicéridos y HDL-colesterol plasmáticos), así como con leptina, adiponectina y TNF-α. La concentración plasmática de ácido úrico fue significativamente más elevada en los niños obesos que en los controles y, cuando se ajustó por sexo, edad e índice de masa corporal, los niveles de ácido úrico se asociaron con el pliegue tricipital y la resistencia inulínica, y negativamente con la adiponectina. En el análisis de regresión múltiple, el índice de masa corporal, el HDL-colesterol y la adiponectina fueron predictores independientes del ácido úrico plasmático. En conclusión, los niveles elevados de ácido úrico en niños obesos en edad prepuberal, comparado con los de los niños normales, representan una alteración metabólica temprana asociada con la resistencia insulínica.This work was supported by the Spanish Ministry of Health and Consumer Affairs, the Spanish National Program for Scientific Research, Development, and Technological Innovation (I+D+I), and the Instituto de Salud Carlos III (Spanish National Health Research Institute), FEDER co-financed Project No. PI 051968. Mercedes Gil-Campos was a research scientist appointed on a training contract funded by the Carlos III Health Research Institute

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

Envejecimiento animal

We review herein the concept of aging in Metazoans, showing the large diversity of cases that prevents the establishment of a general rule for the Animal Kingdom. We describe cases of species that never become old, other that show neglecting senescence and other that develop degenerative processes and decreased or absent fecundity with age. We also review the hypotheses that try to explain the evolutionary conservation of senescence processes that decrease the fitness of the animal as well as the physiological mechanisms involved in them.Hacemos una revisión del concepto de envejecimiento en los Metazoos y mostramos la existencia de una gran diversidad de casos que impiden establecer una regla general para este concepto en el Reino Animal. Describimos casos de especies en las que no existe envejecimiento, otras que muestran senescencia insignificante y otras en las que se producen fenómenos de senescencia con disminución o desaparición de la fecundidad. Discutimos también las distintas hipótesis para explicar la conservación evolutiva de procesos de senescencia que disminuyen la aptitud del individuo, así como los mecanismos fisiológicos implicados en dichos procesos

A population of hematopoietic stem cells derives from GATA4-expressing progenitors located in the placenta and lateral mesoderm of mice

GATA transcription factors are expressed in the mesoderm and endoderm during development. GATA1-3, but not GATA4, are critically involved in hematopoiesis. An enhancer (G2) of the mouse Gata4 gene directs its expression throughout the lateral mesoderm and the allantois, beginning at embryonic day 7.5, becoming restricted to the septum transversum by embryonic day 10.5, and disappearing by midgestation. We have studied the developmental fate of the G2-Gata4 cell lineage using a G2-Gata4Cre;R26REYFP mouse line. We found a substantial number of YFP+ hematopoietic cells of lymphoid, myeloid and erythroid lineages in embryos. Fetal CD41+ /cKit+ /CD34+ and Lin– /cKit+ /CD31+ YFP+ hematopoietic progenitors were much more abundant in the placenta than in the aorta-gonad-mesonephros area. They were clonogenic in the MethoCult assay and fully reconstituted hematopoiesis in myeloablated mice. YFP+ cells represented about 20% of the hematopoietic system of adult mice. Adult YFP+ hematopoietic stem cells constituted a long-term repopulating, transplantable population. Thus, a lineage of adult hematopoietic stem cells is characterized by the expression of GATA4 in their embryonic progenitors and probably by its extraembryonic (placental) origin, although GATA4 appeared not to be required for hematopoietic stem cell differentiation. Both lineages basically showed similar physiological behavior in normal mice, but clinically relevant properties of this particular hematopoietic stem cell population should be checked in physiopathological conditions.España Ministerio de Ecomomía BFU2014-52299-PEspaña Instituto de Salud Carlos III RD12/0019-002

Role of vitamin A/retinoic acid in regulation of embryonic and adult hematopoiesis

Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system