Oligogenic inheritance of a human heart disease involving a genetic modifier.

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the , , and genes.

Spontaneous Closure of a Secundum Atrial Septal Defect.

Spontaneous closure of an atrial septal defect (ASD) is well described in pediatric cardiology but may be less familiar to adult internists and cardiologists. We report a moderately sized 6-mm ASD that closed spontaneously without intervention. A literature review found that a smaller defect size and an early age of diagnosis are the most important predictors of closure.

Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes.

Syndecan-4 signaling at a glance.

Syndecan-4, a ubiquitous cell surface proteoglycan, mediates numerous cellular processes through signaling pathways that affect cellular proliferation, migration, mechanotransduction and endocytosis. These effects are achieved through syndecan-4 functioning as both a co-receptor for the fibroblast growth factor receptors (FGFR1-FGFR4) and its ability to independently activate signaling pathways upon ligand binding. As an FGFR co-receptor, syndecan-4 strengthens the duration and intensity of downstream signaling upon ligand binding; this is particularly evident with regard to mitogen-activated protein kinase (MAPK) signaling.

Syndecan 4 regulates FGFR1 signaling in endothelial cells by directing macropinocytosis.

Fibroblast growth factor 2 (FGF2) induces endothelial cell migration and angiogenesis through two classes of receptors: receptor tyrosine kinases, such as FGF receptor 1 (FGFR1), and heparan sulfate proteoglycans, such as syndecan 4 (S4). We examined the distinct contributions of FGFR1 and S4 in shaping the endothelial response to FGF2. S4 determined the kinetics and magnitude of FGF2-induced mitogen-activated protein kinase (MAPK) signaling by promoting the macropinocytosis of the FGFR1-S4-FGF2 signaling complex.

Auxiliary and autonomous proteoglycan signaling networks.

Proteoglycans represent a structurally heterogeneous family of proteins that typically undergo extensive posttranslational modification with sulfated sugar chains. Although historically believed to affect signaling pathways exclusively as growth factor coreceptors, proteoglycans are now understood to initiate and modulate signal transduction cascades independently of other receptors. From within the extracellular matrix, proteoglycans are able to shield protein growth factors from circulating proteases and establish gradients that guide cell migration.

Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway.

Fibroblast growth factor 2 (FGF2) is a major regulator of developmental, pathological, and therapeutic angiogenesis. Its activity is partially mediated by binding to syndecan 4 (S4), a proteoglycan receptor. Angiogenesis requires polarized activation of the small guanosine triphosphatase Rac1, which involves localized dissociation from RhoGDI1 and association with the plasma membrane.

Direct allosteric regulation between the GAF domain and catalytic domain of photoreceptor phosphodiesterase PDE6.

Photoreceptor cGMP phosphodiesterase (PDE6) is the central enzyme in the visual transduction cascade. The PDE6 catalytic subunit contains a catalytic domain and regulatory GAF domains. Unlike most GAF domain-containing cyclic nucleotide phosphodiesterases, little is known about direct allosteric communication of PDE6.

Non-canonical fibroblast growth factor signalling in angiogenesis.

Whereas fibroblast growth factors (FGFs) classically transmit their signals via high-affinity tyrosine kinase receptors (FGFR1-4), recent evidence strongly implicates non-tyrosine kinase receptors (NTKR) or cell-surface FGFR-interacting proteins as important players in FGF signalling. Although NTKR have lower affinity for FGFs in comparison with cognate tyrosine kinase receptors, because of their high abundance they can effectively bind FGFs and produce unique biological effects independent of FGFRs. A prime example of such NTKR is the syndecan family of plasma membrane proteoglycans and, in particular, syndecan-4, which transmits FGF signalling via a protein kinase Calpha pathway.

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice.

Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is poorly understood. To explore the relationship between cardiac vasculature and normal heart size, we generated a transgenic mouse with a regulatable expression of the secreted angiogenic growth factor PR39 in cardiomyocytes. A significant change in adult mouse EC mass was apparent by 3 weeks following PR39 induction.

Minocycline decreases in vitro microglial motility, beta1-integrin, and Kv1.3 channel expression.

Minocycline is a semisynthetic, tetracycline derivative that exerts anti-inflammatory and neuroprotective effects unrelated to its anti-microbial action. We have previously shown that minocycline prevented peripheral nerve injury-induced mechanical allodynia. Minocycline's mechanisms of action as a neuroprotective and anti-allodynic agent are unknown.

Selective regulation of arterial branching morphogenesis by synectin.

Branching morphogenesis is a key process in the formation of vascular networks. To date, little is known regarding the molecular events regulating this process. We investigated the involvement of synectin in this process.

Syndecan-4 clustering induces cell migration in a PDZ-dependent manner.

Cell migration is a dynamic process involving formation of a leading edge in the direction of migration and adhesion points from which tension is generated to move the cell body forward. At the same time, disassembly of adhesion points occurs at the back of the cell, a region known as the trailing edge. Syndecan-4 (S4) is a transmembrane proteoglycan thought to be involved in the formation of focal adhesions.