New developments in adult congenital heart disease

Congenital heart disease (CHD) affects 0.8% of live births and over the past decades technical improvements and large-scale repair has led to increased survival into adulthood of over 95% of the new-born. A new group of patients, those who survived their congenital heart defect, has emerged but late complications including heart failure, pulmonary hypertension (PH), arrhythmias, aneurysms and endocarditis appeared numerous, with a huge impact on mortality and morbidity. However, innovations over the past years have changed the landscape of adult CHD dramatically. In the diagnostic process important improvements have been made in the use of MRI, biomarkers, e‑health concepts and 3D visualisation of anatomy. Care is now concentrated in specialised centres, with a continuous emphasis on education and the introduction of weekly multidisciplinary consultations on diagnosis and intervention. Surgery and percutaneous intervention have been refined and new concepts applied, further reducing the burden of the congenital malformations. Research has matured from case series to global networks. Currently, adults with CHD are still facing high risks of early mortality and morbidity. By global collaboration and continuous education and development and innovation of our diagnostic and therapeutic arsenal, we will improve the perspectives of these young patients.

     

New developments in the field of cystic kidney diseases

For quite some time the field of polycystic kidney disease has led a life at the fringe of kidney research, but with the cloning of the PKD1 and many other genes this situation has dramatically changed. Polycystic kidney disease often is a syndromic disease affecting a variety of organs in addition to the kidney. Most of the proteins involved in polycystic kidney disease have been localized to the primary cilium, an extension at the apical membrane of renal tubular epithelial cells, which may serve chemo- and mechanosensory functions. It is speculated that primary cilia and their associated proteins play a role in determining the proper tubular geometry.     

Geft is dispensable for the development of the second heart field

Geft is a guanine nucleotide exchange factor, which can specifically activate Rho family of small GTPase by catalyzing the exchange of bound GDP for GTP. Geft is highly expressed in the excitable tissue as heart and skeletal muscle and plays important roles in many cellular processes, such as cell proliferation, migration, and cell fate decision. However, the in vivo role of Geft remains unknown. Here, we generated a Geft conditional knockout mouse by flanking exons 5-17 of Geft with loxP sites. Cre-mediated deletion of the Geft gene in heart using Mef2c-Cre transgenic mice resulted in a dramatic decrease of Geft expression. Geft knockout mice develop normally and exhibit no discernable phenotype, suggesting Geft is dispensable for the development of the second heart field in mouse. The Geft conditional knockout mouse will be a valuable genetic tool for uncovering the in vivo roles of Geft during development and in adult homeostasis. [BMB reports 2012; 45(3): 153-158].     

Hox genes define distinct progenitor sub-domains within the second heart field

Much of the heart, including the atria, right ventricle and outflow tract (OFT) is derived from a progenitor cell population termed the second heart field (SHF) that contributes progressively to the embryonic heart during cardiac looping. Several studies have revealed anterior-posterior patterning of the SHF, since the anterior region (anterior heart field) contributes to right ventricular and OFT myocardium whereas the posterior region gives rise to the atria. We have previously shown that Retinoic Acid (RA) signal participates to this patterning. We now show that Hoxb1, Hoxa1, and Hoxa3, as downstream RA targets, are expressed in distinct sub-domains within the SHF. Our genetic lineage tracing analysis revealed that Hoxb1, Hoxa1 and Hoxa3-expressing cardiac progenitor cells contribute to both atria and the inferior wall of the OFT, which subsequently gives rise to myocardium at the base of pulmonary trunk. By contrast to Hoxb1^Cre, the contribution of Hoxa1-enhIII-Cre and Hoxa3^Cre-labeled cells is restricted to the distal regions of the OFT suggesting that proximo-distal patterning of the OFT is related to SHF sub-domains characterized by combinatorial Hox genes expression. Manipulation of RA signaling pathways showed that RA is required for the correct deployment of Hox-expressing SHF cells. This report provides new insights into the regulatory gene network in SHF cells contributing to the atria and sub-pulmonary myocardium.     

Pulmonary endoderm,second heart field and the morphogenesis of distal outflow tract in mouse embryonic heart

The second heart field (SHF), foregut endoderm and sonic hedgehog (SHH) signaling pathway are all reported to associate with normal morphogenesis and septation of outflow tract (OFT). However, the morphological relationships of the development of foregut endoderm and expression of SHH signaling pathway members with the development of surrounding SHF and OFT are seldom described. In this study, serial sections of mouse embryos from ED9 to ED13 (midgestation) were stained with a series of marker antibodies for specifically highlighting SHF (Isl‐1), endoderm (Foxa2), basement membrane (Laminin), myocardium (MHC) and smooth muscle (α‐SMA) respectively, or SHH receptors antibodies including patched1 (Ptc1), patched2 (Ptc2) and smoothened, to observe the spatiotemporal relationship between them and their contributions to OFT morphogenesis. Our results demonstrated that the development of an Isl‐1 positive field in the splanchnic mesoderm ventral to foregut, a subset of SHF, is closely coupled with pulmonary endoderm or tracheal groove, the Isl‐1 positive cells surrounding pulmonary endoderm are distributed in a special cone‐shaped pattern and take part in the formation of the lateral walls of the intrapericardial aorta and pulmonary trunk and the transient aortic‐pulmonary septum, and Ptc1 and Ptc2 are exclusively expressed in pulmonary endoderm during this Isl‐l positive field development, suggesting special roles played in inducing the Isl‐l positive field formation by pulmonary endoderm. It is indicated that pulmonary endoderm plays a role in the development and specification of SHF in midgestation, and that pulmonary endoderm‐associated Isl‐l positive field is involved in patterning the morphogenesis and septation of the intrapericardial arterial trunks.     

An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart

In order to understand how secreted signals regulate complex morphogenetic events, it is crucial to identify their cellular targets. By conditional inactivation of Fgfr1 and Fgfr2 and overexpression of the FGF antagonist sprouty 2 in different cell types, we have dissected the role of FGF signaling during heart outflow tract development in mouse. Contrary to expectation, cardiac neural crest and endothelial cells are not primary paracrine targets. FGF signaling within second heart field mesoderm is required for remodeling of the outflow tract: when disrupted, outflow myocardium fails to produce extracellular matrix and TGFbeta and BMP signals essential for endothelial cell transformation and invasion of cardiac neural crest. We conclude that an autocrine regulatory loop, initiated by the reception of FGF signals by the mesoderm, regulates correct morphogenesis at the arterial pole of the heart. These findings provide new insight into how FGF signaling regulates context-dependent cellular responses during development.     

Recent developments in the hammerhead ribozyme field.

Developments in the hammerhead ribozyme field during the last two years are reviewed here. New results on the specificity of this ribozyme, the mechanism of its action and on the question of metal ion involvement in the cleavage reaction are discussed. To demonstrate the potential of ribozyme technology examples of the application of this ribozyme for the inhibition of gene expression in cell culture, in animals, as well as in plant models are presented. Particular emphasis is given to critical steps in the approach, including RNA site selection, delivery, vector development and cassette construction.     

Recent developments in the field of iron-sulfur proteins

This review considers recent information, in the following order, on complex proteins containing Fe-S clusters together with other prosthetic groups, on hydrogenases, unexpected functions of Fe-S clusters, novel cluster types, protein structures furnishing the cluster ligands, evolutionary aspects, and spectroscopic methods and theoretical approaches used or developed in the study of Fe-S proteins.     

New developments in silvichemicals

A discussion of the activities of Crown Zellerbach Corporation in the field of developing, producing and worldwide marketing of pure chemicals of commerce from the forest, including comments on some new chemicals being developed.     

New developments in cytogenetics

Novel methods allowing to analyze the human genome make it possible to assess old questions such as the molecular basis of structural chromosome anomalies and the diathesis to aneuploidy. The architecture of the human genome as unravelled by the human genome sequencing project allows to explain the recurrence of microdeletions and microduplications caused by a non allelic homologous recombination involving segmental duplications created during the evolution of primates. This structural feature of the human genome is associated with a novel class of genetic diseases called genomic disorders as opposed to genetic diseases due to gene mutations. The study of the parental and cellular origin of aneuploidy shed new light on the different mechanisms controlling meiosis in man and woman. In addition it contributes to define the role of maternal age and genetic recombination on the behavior of chromosomes during meiosis. These new data greatly contribute to our understanding of human chromosomal diseases.