Diabetes results from the absolute or relative deficiency of insulin-producing β cells. The prospect that non-β pancreatic cells could be harnessed to become β cells has led to interest in understanding the plasticity of pancreatic cells. Recent studies, however, have shown that adult β cells are largely derived from preexisting β cells. In this issue of the JCI, Desai et al. show that acinar cells, the major cell type in the pancreas, do not contribute to new β cells formed during pancreatic regeneration (see the related article beginning on page 971). These studies suggest that the fate of adult pancreatic cell lineages is immutable. However, also in this issue of the JCI, Collombat et al. demonstrate that inducing a single transcription factor named Arx in adult β cells causes these cells to undergo massive transdifferentiation into α and pancreatic polypeptide endocrine cells (see the related article beginning on page 961). This finding points to an unexpected plasticity of postnatal pancreatic endocrine cells.
Jorge Ferrer, Mercè Martín, Joan Marc Servitja
Erythropoietin (EPO) is the hormonal regulator of red cell production and provided the paradigm for oxygen-regulated gene expression that led to the discovery of hypoxia-inducible factor (HIF). In this issue of the JCI, Rankin and colleagues show, using targeted gene inactivation, that induction of Epo expression in murine liver is dependent on the integrity of HIF-2α, and not HIF-1α (see the related article beginning on page 1068). These results demonstrate distinct functions for different HIF-α isoforms that could potentially be exploited in therapeutic approaches to anemia.
Peter J. Ratcliffe
Components of the renin-angiotensin system (RAS) are expressed in a number of areas in the brain involved in cardiovascular control. However, it has been difficult to link RAS actions in circumscribed brain regions to specific physiological functions. In a study appearing in this issue of the JCI, Sakai and associates use a combination of sophisticated transgenic techniques and stereotaxic microinjection of recombinant viral vectors to demonstrate a pivotal role in the regulation of thirst and salt appetite of angiotensin II generated in the subfornical organ in the brain (see the related article beginning on page 1088).
Kelly K. Parsons, Thomas M. Coffman
IFN-γ has long been recognized as a signature proinflammatory cytokine that plays a central role in inflammation and autoimmune disease. There is now emerging evidence indicating that IFN-γ possesses unexpected properties as a master regulator of immune responses and inflammation. In this issue of the JCI, Guillonneau et al. show that indefinite allograft survival induced by CD40Ig treatment is mediated by CD8+CD45RClow T cells through the production of IFN-γ (see the related article beginning on page 1096), supporting the emerging view that IFN-γ is critical in the self-regulation of inflammation. These contradictory roles of IFN-γ, perhaps best understood by the principle of yin and yang, represent one of nature’s paradoxes, whereby the same cytokine functions as an inducer as well as a regulator for inflammation. Understanding this complex process of IFN-γ signaling is essential, as it has therapeutic implications.
The deregulation of homeobox (HOX) genes in acute myeloid leukemia (AML) and the potential for these master regulators to perturb normal hematopoiesis is well established. To date, overexpression of HOX genes in AML has been attributed to specific chromosomal aberrations and abnormalities involving mixed-lineage leukemia (MLL), an upstream regulator of HOX genes. The finding reported in this issue of the JCI by Scholl et al. that caudal-type homeobox transcription factor 2 (CDX2), which is capable of affecting HOX gene expression during embryogenesis, is overexpressed in 90% of patients with AML and induces a transplantable AML in murine models provides an alternative mechanism for HOX-induced leukemogenesis and yields important insights into the hierarchy of HOX gene regulation in AML (see the related article beginning on page 1037).
Kim L. Rice, Jonathan D. Licht
Although it was first described in 1989, our understanding of coenzyme Q10 (CoQ10) deficiency is only now coming of age with the recent first description of the underlying molecular defects. The diverse clinical presentations, classifiable into four major syndromes, raise the question as to whether the deficiencies are primary or secondary. Recent studies, including the one by Mollet, Rötig, and colleagues reported in this issue of the JCI, document molecular defects in three of the nine genes required for CoQ10 biosynthesis, all of which are associated with early and severe clinical presentations (see the related article beginning on page 765). It is anticipated that defects in the other six genes will cause similar early-onset encephalomyopathies. Awareness of CoQ10 deficiency is important because individuals with primary or secondary variants may benefit from oral CoQ10 supplementation.
Salvatore DiMauro, Catarina M. Quinzii, Michio Hirano
Protein accumulation is a hallmark of many neurodegenerative disorders. In Alzheimer’s disease (AD), a hyperphosphorylated form of the protein tau (p-tau) forms intracellular inclusions known as neurofibrillary tangles. Deposits of p-tau have also been found in the brains of patients with Down’s syndrome, supranuclear palsy, and prion disease. Mutations in tau have been causally associated with at least one inherited neurologic disorder, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), implying that tau abnormalities by themselves can be a primary cause of degenerative diseases of the CNS. Removal of these p-tau species may occur by both chaperone-mediated refolding and degradation. In this issue of the JCI, Dickey and colleagues show that a cochaperone protein, carboxyl terminus of Hsp70-interacting protein (CHIP), in a complex with Hsp90 plays an important role in the removal of p-tau (see the related article beginning on page 648). Pharmacologic manipulation of Hsp90 may be used to alleviate p-tau accumulation in disease.
Dmitry Goryunov, Ronald K.H. Liem
The hormone aldosterone increases extracellular fluid volume and blood pressure by activating epithelial Na+ channels (ENaCs). Serum- and glucocorticoid-induced kinase 1 (SGK1) is an aldosterone-stimulated signaling molecule that enhances distal nephron Na+ transport, in part by preventing the internalization of ENaCs from the plasma membrane. In this issue of the JCI, Zhang et al. demonstrate that SGK1 enhances transcription of the α subunit of ENaC by preventing histone methylation, providing an additional mechanism by which SGK1 increases ENaC-mediated Na+ transport in the distal nephron (see the related article beginning on page 773).
David Pearce, Thomas R. Kleyman
Inhaled environmental oxidants, such as ozone and particulates, have been variably linked to epithelial injury, inflammation, and perturbations in lung development, growth, and function. Reactions between ozone and lung surface lipids likely account for exposure-related pathophysiologic sequelae. In this issue of the JCI, Dahl et al. document a previously unrecognized pulmonary defense against inhaled oxidants in mice: macrophage scavenger receptors (SRs) bind proinflammatory oxidized lipids, thereby decreasing pulmonary inflammation (see the related article beginning on page 757). The study adds to our knowledge of diverse lung oxidative processes and identifies a potential regulatory mechanism governing pulmonary inflammation. Further investigations to elucidate more precise mechanisms and to determine the influence of SRs on airway epithelial injury, repair, and remodeling are warranted.
Edward M. Postlethwait
Natural antibodies are autoreactive/polyreactive antibodies believed to be secreted in the absence of xenoantigens. The origin and functional role of this limited and selective autoimmunity are not clear, nor is the specificity and range of autoantigens that drive the development of B cells producing natural antibodies. In this issue of the JCI, Merbl et al. report that in utero, humans generate natural IgM and IgA antibodies that recognize a uniform set of autoantigens (see the related article beginning on page 712), some of which are associated with autoimmune diseases. The authors postulate that this “autoimmunity” at birth favors the emergence of autoimmune diseases in later life. We present a molecular basis for the limited and common repertoire of antibodies produced by fetal B cells, which may be distinct from the abnormalities in B cell development described in patients with autoimmune diseases.
Eric Meffre, Jane E. Salmon
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