Commentary
Abstract
Male and female external genitalia appear identical early in gestation. Testosterone exposure at 8–12 weeks’ gestation causes male differentiation. Female fetuses virilize if their adrenals secrete excessive levels of androgens, as occurs in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This can be ameliorated by administering dexamethasone to the mother. A study by Goto et al. in this issue of the JCI provides a rationale for this treatment by demonstrating that the fetal hypothalamic-pituitary-adrenal axis is fully functional when the genitalia differentiate (see the related article beginning on page 953). Dexamethasone suppresses this axis, reducing abnormal secretion of adrenal androgens. Their results also show that cortisol synthesis by the fetal adrenal decreases after this period, allowing the adrenal to secrete high levels of dehydroepiandrosterone, an androgen precursor. However, this does not virilize female fetuses because androgens are aromatized to estrogens in the placenta. Thus normal sexual differentiation requires exquisite timing of fetal cortisol and androgen secretion versus placental capacity for aromatization.
Authors
Perrin C. White
Abstract
RA is a quintessential autoimmune disease with a growing number of cells, mediators, and pathways implicated in this tissue-injurious inflammation. Now Kuhn and colleagues have provided convincing evidence that autoantibodies reacting with citrullinated proteins, known for their sensitivity and specificity as biomarkers in RA, enhance tissue damage in collagen-induced arthritis (see the related article beginning on page 961). This study adds yet another soldier to the growing army of autoaggressive mechanisms that underlie RA. With great success researchers have dismantled the pathogenic subunits of RA, adding gene to gene, molecule to molecule, and pathway to pathway in an ever more complex scheme of dysfunction. The complexity of the emerging disease model leaves us speechless. It seems that with this wealth of data available, we need to develop a new theory for this disease. We may want to seek guidance from our colleagues in physics and mathematics who have successfully integrated their knowledge of elementary particles and the complexity of their interacting forces by formulating the string theory.
Authors
Cornelia M. Weyand, Jörg J. Goronzy
Abstract
The aspartyl protease renin was first isolated from the kidney by Tigerstedt more than a century ago. In the kidney, renin secretion is tightly linked to sodium intake and renal perfusion pressure, reflecting the important role of the renin-angiotensin system (RAS) in controlling body fluid volume and blood pressure. The study by Mackins et al. in this issue of the JCI describes a novel source of renin: the mast cell (see the related article beginning on page 1063). This discovery suggests a distinct pathway for activation of the RAS that may have a particular impact on the pathogenesis of chronic tissue injury as well as more acute pathology such as arrhythmias in the heart.
Authors
Thu H. Le, Thomas M. Coffman
Abstract
During vertebrate development, mesenchymal progenitors capable of forming bone, cartilage, muscle, fat, or tendon arise from either neural crest or somitic mesoderm. Transcriptional programs that specify mesenchymal cell fates are initiated and modified by paracrine cues provided by TGF-β superfamily members and mediated in part via the regulated assembly of Smad-containing multiprotein transcription factor complexes. In this issue of the JCI, Hoffmann and colleagues have identified that Smad8 activation drives tendon formation from C3H10T1/2 cells, a murine cell line that recapitulates many features of normal multipotent mesenchymal cells (see the related article beginning on page 940). Cells programmed to the tenocyte cell fate in vitro formed tenogenic grafts in vivo. These results add to the accumulating evidence that proliferating, multipotent mesenchymal progenitor cells can be programmed to yield multiple cell types — e.g., osteoblasts, myocytes, chondrocytes, and tenocytes — that may be useful in cell-based therapeutic approaches to musculoskeletal diseases.
Authors
Dwight A. Towler, Richard H. Gelberman
Abstract
Genetic diseases often reveal the physiological roles of the affected proteins. The identification of mutations in the nuclear envelope proteins lamin A and lamin C as the cause of a diverse group of human diseases has expanded our understanding of the lamin proteins from being merely structural elements of the cell nucleus and has implicated them in novel cellular functions including signal transduction and gene expression. However, it now appears that the physiological relevance of one of the lamin proteins in organismal function has been overestimated. In this issue of the JCI, Fong et al. demonstrate that lamin A–deficient mice are phenotypically normal (see the related article beginning on page 743). The good news is these findings open the door to a new strategy for the therapeutic treatment of diseases caused by mutations in lamin A, such as muscular dystrophies and some types of premature aging syndromes.
Authors
Paola Scaffidi, Tom Misteli
Abstract
Ca2+ plays a pivotal role in both excitation-contraction coupling (ECC) and activation of Ca2+-dependent signaling pathways. One of the remaining questions in cardiac biology is how Ca2+-dependent signaling pathways are regulated under conditions of continual Ca2+ transients that mediate cardiac contraction during each heartbeat. Ca2+-calmodulin–dependent protein kinase II (CaMKII) activation and its ability to regulate histone deacetylase 5 (HDAC5) nuclear shuttling represent a critical Ca2+-dependent signaling circuit for controlling cardiac hypertrophy and heart failure, yet the mechanism of activation by Ca2+ is not known. In this issue of the JCI, Wu et al. convincingly demonstrate that the inositol 1,4,5-trisphosphate receptor (InsP3R) is involved in local control of Ca2+ for activating CaMKII in the nuclear envelope of adult ventricular cardiac myocytes (see the related article beginning on page 675). The overall paradigm that is demonstrated is the best example of a molecular mechanism whereby signaling is directly regulated by a local Ca2+ pool that is disparate or geometrically insensitive to cytosolic Ca2+ underlying each contractile cycle.
Authors
Jeffery D. Molkentin
Abstract
The anaphylatoxins complement component 3a and 5a (C3a and C5a, respectively) are classically seen as proinflammatory mediators of allergic asthma that recruit inflammatory cells, induce edema, and cause bronchoconstriction. A few years ago, controversy arose when it was shown that C5-deficient mice were more susceptible to experimental asthma compared with C5-sufficient mice. In a study by Köhl et al. in this issue of the JCI, it is shown in a series of truly “complementary” experiments that C5a receptor (C5aR) blockade promotes Th2 sensitization upon first exposure to inhaled allergen, whereas C5aR blockade during established inflammation suppresses the cardinal features of asthma (see the related article beginning on page 783). Blockade of C5aR alters the function of airway DCs, crucial for inducing and maintaining Th2 responses in the lung. Targeting C5aR as a treatment for established asthma could be beneficial, but might be accompanied by sensitization to novel antigens.
Authors
Bart N. Lambrecht
Going in circles: conserved mechanisms control radial patterning in the urinary and digestive tracts
Abstract
Radial patterning in the urinary tract and gut depends on reciprocal signaling between epithelial cells, which form mucosa, and mesenchyme, which forms smooth muscle and connective tissue. These interactions depend on sonic hedgehog (Shh), which is secreted by epithelial cells and induces expression of bone morphogenetic protein 4 (Bmp4), a signaling molecule required for differentiation of smooth muscle progenitors. Patterning of the specialized mucosa lining the anterior-posterior (A-P) axis may be controlled independently by regionally expressed mesenchymal transcription factors. A study by Airik et al. in this issue of the JCI reveals that T-box 18 (Tbx18), a transcription factor selectively expressed in ureteral mesenchyme, regulates smooth muscle differentiation by maintaining Shh1 responsiveness in mesenchymal progenitors (see the related article beginning on page 663). Deletion of Tbx18 resulted in defective urothelial differentiation at the level of the ureter, suggesting that Tbx18 acts via mesenchyme as an important regulator of A-P patterning in the urinary tract.
Authors
Cathy Mendelsohn
Abstract
The precise role of erythropoietin receptor–activated (EpoR-activated) Stat5 in the regulation of erythropoiesis remains unclear. In this issue of the JCI, Menon and colleagues present new experimental data that indicate a distinct role for Stat5 in the regulation of stress-induced erythropoiesis, such as during acute anemic states (see the related article beginning on page 683). A critical function for Stat5 is to promote cell survival, possibly through transcriptional induction of the antiapoptotic protein Bcl-x. In the present experimental system, erythropoietin-Stat5 signals did not induce Bcl-x expression but did induce oncostatin-M. Moreover, oncostatin-M was found to enhance survival of erythroid progenitors. This work differentiates between steady-state (or homeostatic) erythropoiesis and stress-induced erythropoiesis at the level of EpoR signaling.
Authors
Gregory D. Longmore
Abstract
The ghrelin receptor is known from in vitro studies to signal in the absence of the hormone ghrelin at almost 50% of its maximal capacity. But, as for many other 7-transmembrane receptors, the in vivo importance of this ligand-independent signaling has remained unclear. In this issue of the JCI, Pantel et al. find that a natural mutation in the ghrelin receptor, Ala204Glu, which is associated with a selective loss of constitutive activity without affecting ghrelin affinity, potency, or efficacy, segregates in 2 families with the development of short stature (see the related article beginning on page 760). By combination of the observations from this study with those related to the phenotype of subjects carrying another natural ghrelin receptor mutation, Phe279Leu, having identical molecular-pharmacological properties, it is proposed that selective lack of ghrelin receptor constitutive signaling leads to a syndrome characterized not only by short stature, but also by obesity that apparently develops during puberty.
Authors
Birgitte Holst, Thue W. Schwartz
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