Roles for the Type 2 diabetes-associated genes C2CD4A and C2CD4B in the control of insulin secretion

Genome-wide Association Studies (GWAS) have identified several SNPs in human chromosome 15 at the C2CD4A/C2CD4B/VPS13C locus associated with increased proinsulin levels and type 2 diabetes (T2D) risk. A recent in vivo study has shown that murine Vpc13c has a minor role in glucose homeostasis. Therefore, in this study, I sought to investigate the roles of C2CD4A and C2CD4B in glucose homeostasis and insulin secretion. C2CD4A and C2CD4B have been predicted to encode nucleus-localised calcium-binding proteins in endothelial cells. To investigate the role of these genes in pancreatic β-cells, we first addressed their subcellular localisation. Our results suggested a novel role for these genes products since they showed localisation at the plasma membrane in addition to the nucleus as shown previously in endothelial cells. We also found that C2CD4A translocates from the cytoplasm to the plasma membrane in response to an elevation in intracellular free calcium. This suggests that the C2 domain of this protein binds to calcium and membrane phospholipids. We also studied the role of C2cd4b in vivo. Our data showed that a lack of C2cd4b in female mice leads to impaired glucose tolerance, caused by a significantly decreased plasma insulin level. In these mice, we also observed a significant reduction of follicle-stimulating hormone (FSH). In contrast to the latter data, C2cd4a null mice did not present any glucose intolerance phenotype, suggesting a minor role for this gene in glucose homeostasis. However, in humans, deletion of this gene from human pancreas-derived β-cells caused an impairment in insulin secretion. Taken together, our data demonstrate a novel role for these genes in the control of insulin secretion and glucose homeostasis. Further studies investigating the structures, their specific functions and interacting partners may demonstrate the mechanisms of action of the nearby T2D variants and open new avenues for the treatment of T2D.Open Acces

The Development of Linguistic Competences for Employability: A Training Project for Teachers

AbstractEmployability is a new concept that has just appeared in the Spanish educational system. Its rising importance is due to European Union educational policies which aim to provide young people with training that enables them to take part successfully in the present and future working world.This paper argues for the need to develop employability from the very start of formal education, and within this, we highlight the importance of developing linguistic competence among pre-school and primary pupils as a key element for favouring employability.To be able to do so, the teaching staff must be trained using quality education to enable them to work effectively on this competence. In this paper we present how a training program, with a specific European dimension, has been designed by a state school from the Valencian Community, to serve as a model for other schools concerned about the development of a linguistic competence that helps to improve both teachers’ and pupils’ employability

Sox2(+) Stem/Progenitor Cells in the Adult Mouse Pituitary Support Organ Homeostasis and Have Tumor-Inducing Potential

SummarySox2+ adult mouse pituitary cells can self-renew and terminally differentiate in vitro, but their physiological role in vivo and possible contribution to oncogenesis remain largely unknown. Using genetic lineage tracing, we show here that the Sox2+ cell compartment of both the embryonic and adult pituitary contains stem/progenitor cells that are able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during postnatal life. In addition, we show that targeted expression of oncogenic β-catenin in Sox2+ cells gives rise to pituitary tumors, but, unexpectedly, the tumor mass is not derived from the Sox2+ mutation-sustaining cells, suggesting a paracrine role of Sox2+ cells in pituitary oncogenesis. Our data therefore provide in vivo evidence of a role for Sox2+ stem/progenitor cells in long-term physiological maintenance of the adult pituitary, and highlight an unexpected non-cell-autonomous role for these cells in the induction of pituitary tumors.Video Abstrac

Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans

Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/β-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo–pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke’s pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with β-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH