Molecular and genetic studies around the turn of this century have revolutionized the field of cardiac development. We now know that the primary heart tube, as seen in the early embryo contains little more than the precursors for the left ventricle, whereas the precursor cells for the remainder of the cardiac components are continuously added, to both the venous and arterial pole of the heart tube, from a single center of growth outside the heart. While the primary heart tube is growing by addition of cells, it does not show significant cell proliferation, until chamber differentiation and expansion starts locally in the tube, by which the chambers balloon from the primary heart tube. The transcriptional repressors Tbx2 and Tbx3 locally repress the chamber-specific program of gene expression, by which these regions are allowed to differentiate into the distinct components of the conduction system. Molecular genetic lineage analyses have been extremely valuable to assess the distinct developmental origin of the various component parts of the heart, which currently can be unambiguously identified by their unique molecular phenotype. Despite the enormous advances in our knowledge on cardiac development, even the most common congenital cardiac malformations are only poorly understood. The challenge of the newly developed molecular genetic techniques is to unveil the basic gene regulatory networks underlying cardiac morphogenesis.
Follistatin-like 1 (Fstl1) is a secreted protein of the BMP inhibitor class. During development, expression of Fstl1 is already found in cleavage stage embryos and becomes gradually restricted to mesenchymal elements of most organs during subsequent development. Knock down experiments in chicken and zebrafish demonstrated a role as a BMP antagonist in early development. To investigate the role of Fstl1 during mouse development, a conditional Fstl1 KO allele as well as a Fstl1-GFP reporter mouse were created. KO mice die at birth from respiratory distress and show multiple defects in lung development. Also, skeletal development is affected. Endochondral bone development, limb patterning as well as patterning of the axial skeleton are perturbed in the absence of Fstl1. Taken together, these observations show that Fstl1 is a crucial regulator in BMP signalling during mouse development.
Follistatin-like 1 (Fstl1) is a member of the secreted protein acidic rich in cysteins (SPARC) family and has been implicated in many different signaling pathways, including bone morphogenetic protein (BMP) signaling. In many different developmental processes like, dorso-ventral axis establishment, skeletal, lung and ureter development, loss of function experiments have unveiled an important role for Fstl1. Fstl1 largely functions through inhibiting interactions with the BMP signaling pathway, although, in various disease models, different signaling pathways, like activation of pAKT, pAMPK, Na/K-ATPase, or innate immune responses, are linked to Fstl1. How Fstl1 inhibits BMP signaling remains unclear, although it is known that Fstl1 does not function through a scavenging mechanism, like the other known extracellular BMP inhibitors such as noggin. It has been proposed that Fstl1 interferes with BMP receptor complex formation and as such inhibits propagation of the BMP signal into the cell. Future challenges will encompass the identification of the factors that determine the mechanisms that underlie the fact that Fstl1 acts by interfering with BMP signaling during development, but through other signaling pathways during disease.
T he right ventricular outflow tract (RVOT) is the main origin of arrhythmias in the Brugada syndrome.1 The mechanism underlying arrhythmias in Brugada syndrome is debated but most likely involves conduction delay or block in the presence of subtle structural discontinuities. 2This arrhythmogenic substrate is modulated by variations or mutations in ion channels and other genes.3 The electrocardiographic signs and arrhythmias often only become evident after application of sodium channel blockers.4 Why arrhythmias in patients with Brugada syndrome preferentially originate in the RVOT is unclear.During development, the RVOT forms from the embryonic outflow tract. 5 The embryonic outflow tract is a slowly conducting structure with low expression levels of connexin43, connexin40, and of the cardiac sodium channel protein α subunit (Scn5a).6,7 Low expression of Scn5a and connexin43 reduces the safety of propagation, also known as conduction reserve, and increases the susceptibility for arrhythmias. 8 We hypothesize that the adult RVOT myocardium retains aspects of this embryonic outflow tract phenotype and that these embryonic aspects contribute to lower conduction reserve in the RVOT.We investigated the expression pattern of genes associated with the embryonic outflow tract phenotype and with conduction in the mouse RVOT, in relation to conduction velocity, during development and in the adult heart. Furthermore, we investigated the functional consequences of reduced sodium current on RVOT conduction by pharmacological sodium channel blockade and in a mouse model with a human cardiac sodium channel mutation associated with the Brugada syndrome. Cellular Biology
We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.
Escherichia coli is the most common pathogen found in urinary tract infections (UTIs), mainly affecting children and women. We report that CD44, a hyaluronic acid (HA) binding protein that mediates cell-cell and cell-matrix interactions, facilitates the interaction of E. coli with urothelial cells and thus the infection of the host. We found that CD44 is constitutively expressed on urothelial cells and that HA accumulates in E. coli-induced UTI. In CD44-deficient mice, the bacterial outgrowth was dramatically less compared with wild-type mice despite similar granulocyte influx in the bladder and in the kidney as well as comparable cytokines/chemokines levels in both genotypes. E. coli was able to bind HA, which adhered to CD44-positive tubular epithelial cells. Most importantly, the interaction of CD44 on tubular epithelial cells with HA facilitated the migration of E. coli through the epithelial monolayer. The results provide evidence that CD44 on urothelial cells facilitates E. coli UTI. Disruption of the interaction between CD44 and HA in the bladder may provide a new approach to prevent and to treat UTI.
We report on a mouse model in which deletion of Fstl1 from the endocardial/endothelial lineage results in deformed mitral valves, which cause regurgitation, heart failure, and early cardiac death. The findings provide a potential molecular target for the clinical research into myxomatous mitral valve disease.
As CD44 is involved in the activation, proliferation, adhesion, and extravasation of lymphocytes, we hypothesized that CD44 could be involved in the pathogenesis of acute renal allograft rejection. Renal biopsies and plasma were collected from patients suffering an episode of acute renal allograft rejection. CD44 and its ligands, hyaluronic acid (HA) and osteopontin, were analyzed retrospectively by immunohistochemistry and, computer-aided, morphometric analysis. Soluble CD44 (sCD44) and osteopontin in the plasma were determined by enzyme-linked immunosorbent assay. During acute rejection episodes, CD44 and its ligands, HA and osteopontin, were upregulated in the renal allograft. Also, increased sCD44 plasma levels were observed, which correlated with both tubular expression of CD44 and the extent of infiltrate. No differences could be detected between the different pathologic grades of rejection. Upregulation of tubular CD44 and increased levels of circulating sCD44 may reflect a common pathogenic mechanism during acute renal rejection and could be useful markers in the diagnosis of acute renal rejection.
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