Fatty acid synthase is a metabolic oncogene targetable in malignant peripheral nerve sheath tumors.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target.

Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development.

Mutations within the protein tyrosine phosphatase, SHP2, which is encoded by PTPN11, cause a significant proportion of Noonan syndrome (NS) cases, typically presenting with both cardiac disease and craniofacial abnormalities. Neural crest cells (NCCs) participate in both heart and skull formation, but the role of SHP2 signaling in NCC has not yet been determined. To gain insight into the role of SHP2 in NCC function, we ablated PTPN11 specifically in premigratory NCCs.

Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome.

Noonan syndrome (NS) is the most common nonchromosomal genetic disorder associated with cardiovascular malformations. The most prominent cardiac defects in NS are pulmonary valve stenosis and hypertrophic cardiomyopathy. Gain-of-function mutations in the protein tyrosine phosphatase Shp2 have been identified in 50% of NS families.

Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement.

Molecular identity of olfactory bulb interneurons: transcriptional codes of periglomerular neuron subtypes.

Interneurons in the glomerular layer (GL) of the olfactory bulb represent a diverse set of cells, which can be identified by distinct expression of different neurotransmitters as well as calcium binding proteins. Using genetic based fate mapping, we show here that at least three of these different interneurons subtypes (i.e.

Nestin-CreER mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia hypoxia.

The standard method of detecting neurogenesis uses bromodeoxyuridine (BrdU) to label DNA synthesis followed by double labeling with neuronal markers. However, DNA synthesis may occur in events unrelated to neurogenesis including aneuploidy and abortive cell cycle reentry. Hence, it is important to confirm neurogenesis with methods other than BrdU incorporation.

Neural crest cells retain multipotential characteristics in the developing valves and label the cardiac conduction system.

Multipotent neural crest cells (NCCs) are a major extracardiac component of cardiovascular development. Although recognized as contributing cells to the arterial valves at early developmental stages, NCC persistence in the valves at later times or in the adult heart is controversial. We analyzed NCC persistence and contributions to both semilunar and atrioventricular (AV) valves in the mature heart.

Lentiviral vectors pseudotyped with murine ecotropic envelope: increased biosafety and convenience in preclinical research.

Objective: Lentiviral vectors are increasingly used for preclinical models of gene therapy and other forms of experimental transgenesis. Due to the broad tropism and the ability for concentration by ultracentrifugation, most lentiviral vector preparations are produced using the vesicular stomatitis virus glycoprotein (VSV-g) protein as envelope. Recently, Hanawa and colleagues have demonstrated that the ecotropic envelope protein of murine leukemia viruses allows efficient pseudotyping of HIV-1-derived vector particles.

Ras-related signaling pathways in valve development: ebb and flow.

Congenital heart defects affect approximately 1 in every 100 live births, and deficits in the formation of the mitral, tricuspid, and outflow tract valves account for 20-25% of all cardiac malformations. Mutations in genes that affect Ras signaling have been identified in individuals with congenital valve disease associated with Noonan syndrome and neurofibromatosis type 1. Dissection of Ras-related signaling pathways during valvulogenesis provides seminal insight into cellular and molecular mechanisms that contribute to congenital heart disease.

Retinoic acid induces CDK inhibitors and growth arrest specific (Gas) genes in neural crest cells.

Retinoic acid (RA), the active metabolite of vitamin A, regulates cellular growth and differentiation during embryonic development. In excess, this vitamin is also highly teratogenic to animals and humans. The neural crest is particularly sensitive to RA, and high levels adversely affect migration, proliferation and cell death.

Large-scale reprogramming of cranial neural crest gene expression by retinoic acid exposure.

Although retinoic acid (RA), the active form of vitamin A, is required for normal embryonic growth and development, it is also a powerful teratogen. Infants born to mothers exposed to retinoids during pregnancy have a 25-fold increased risk for malformations, nearly exclusively of cranial neural crest-derived tissues. To characterize neural crest cell responses to RA, we exposed murine crest cultures to teratogenic levels of RA and subjected their RNA to microarray-based gene expression profile analysis using Affymetrix MG-U74Av2 GeneChips.

Midgestational lethality in mice lacking the parathyroid hormone (PTH)/PTH-related peptide receptor is associated with abrupt cardiomyocyte death.

PTHrP is a key developmental regulatory protein and a potent vasoactive agent. Previous studies have shown that mice lacking either the Pthrp or the PTH type 1 receptor (Pth1r) gene exhibit severe chondrodysplasia. In addition, in most genetic backgrounds, the receptor null mice die prenatally at midgestation, but the cause of death remains elusive.

Remodeling of gap junctions in mouse hearts hypertrophied by forced retinoic acid signaling.

Background: Beta-MHC-hRARalpha transgenic mice express a constitutively active (truncated) form of the human retinoic acid receptor which triggers development of dilated cardiomyopathy. In those hearts, we studied expression of gap junction proteins in relation to electrical impulse propagation.

Methods And Results: As compared to wildtype mice, hearts of 4-6 month old mice with 7-12 inserted hRARalpha copies are marked by an increased heart weight/body weight- and heart weight/tibia length ratio.

Retinoids and cardiovascular developmental defects.

Vitamin A and related retinoids are critical regulators of normal cardiovascular development. Extreme variations in retinoid levels, too little or too much, dramatically alter embryonic morphogenesis that has teratogenic consequences, including effects on the heart and great vessels. Specific cardiovascular targets of retinoid action include effects on the anteroposterior patterning of the early heart, left-right decisions and cardiac situs, endocardial cushion formation, and, in particular, the neural crest.

Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure.

Objective: Impaired myocyte Ca2+ handling is a common characteristic of failing hearts and increases in calcineurin activity, a Ca2+-sensitive phosphatase, have been implicated in heart failure phenotype. Transgenic mice with cardiac-specific expression of an active form of calcineurin display depressed function, hypertrophy and heart failure. We examined whether defects in cardiomyocyte Ca2+ handling properties contribute to the impaired cardiac function in calcineurin transgenic mice.

Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy.

Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L.