Palisade Endings Are a Constant Feature in the Extraocular Muscles of Frontal-Eyed, But Not Lateral-Eyed, Animals

Purpose To test whether palisade endings are a general feature of mammalian extraocular muscles (EOMs). Methods Thirteen species, some frontal-eyed (human, monkey, cat, and ferret), and others lateral-eyed (pig, sheep, calf, horse, rabbit, rat, mouse, gerbil, and guinea pig) were analyzed. Palisade endings were labeled by using different combinations of immunofluorescence techniques. Three-dimensional reconstructions of immunolabeled palisade endings were done. Results In all frontal-eyed species, palisade endings were a consistent feature in the rectus EOMs. Their total number was high and they exhibited an EOM-specific distribution. In particular, the number of palisade endings in the medial recti was significantly higher than in the other rectus muscles. In the lateral-eyed animals, palisade endings were infrequent and, when present, their total number was rather low. They were only found in ungulates (sheep, calf, pig, and horse) and in rabbit. In rodents (rat, guinea pig, mouse, and gerbil) palisade endings were found infrequently (e.g., rat) or were completely absent. Palisade endings in frontal-eyed species and in some lateral-eyed species (pig, sheep, calf, and horse) had a uniform morphology. They generally lacked α-bungarotoxin staining, with a few exceptions in primates. Palisade endings in other lateral-eyed species (rabbit and rat) exhibited a simplified morphology and bound α-bungarotoxin. Conclusions Palisade endings are not a universal feature of mammalian EOMs. So, if they are proprioceptors, not all species require them. Because in frontal-eyed species, the medial rectus muscle has the highest number of palisade endings, they likely play a special role in convergence

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.IB is funded by Wellcome (WT206194). ATH and SE are the recipients of a Wellcome Trust Senior Investigator award and ATH is employed as a core member of staff within the NIHR funded Exeter Clinical Research Facility and is an NIHR senior investigator. EDF was a Naomi Berrie Fellow in Diabetes Research during the study. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number: 105636/Z/14/Z). CCW holds a Wellcome Trust Intermediate Clinical Fellowship (Grant Number: 105914/Z/14/Z). HH is funded by the Research Foundation-Flanders (FWO), the VUB Research Council and Stichting Diabetes Onderzoek Nederland

Malformations of the great intrathoracic arteries caused by hemodynamic alterations in chick embryos

Angeborene Defekte betreffen oft das Herz und die großen Intrathorakalen Arterien. In meiner Hypothese ging ich davon aus, dass einer abnormen Gefäßkonfiguration eine durch nicht regelhafte Herzentwicklung verursachte Änderung der Hämodynamik in den sich entwickelnden Pharyngealbogenarterien zugrunde liegt. Ziel meiner Arbeit war es diese Hypothese anhand des Hühnchen Models zu testen. Ich entwickelte und evaluierte ein Protokoll zur Manipulation von Herzen früher Embryonen im Entwicklungsstadium Hamburger Hamilton 17 (HH). Ein durch die Manipulation entstandener vorübergehenden Defekt im compact myocardial layer des sich entwickelnden rechten Ventrikels hatte eine Verlangsamung dessen Pumpwirkung und eine Fehlentwicklung des trabeculated layer zur Folge. Eine Evaluierung ergab, dass die durchgeführte Manipulation alleine das Myokard schädigte ohne andere wichtige Strukturen in Mitleidenschaft zu ziehen. Im Entwicklungsstadium HH34 zeigten die Embryonen schwerwiegende Herzfehlbildungen wie ectopia cordis, Ventrikelseptumsdefekte (VSD) oder double - outlet right ventricle (DORV). Außerdem zeigten alle Embryonen Fehlbildungen der großen intrathorakalen Gefäße. Aus den Ergebnissen können folgende Schlüsse gezogen werden: Erstens, Defekte des rechten Ventrikels und des Ausflusstraktes sind mögliche Ursachen für eine abnorme Gefäßkonfiguration der großen intrathorakalen Gefäße. Zweitens, Eine veränderte Hämodynamik im sich entwickelnden Pharyngealbogenarterien - System führt zu einem nicht regelhaften Umbau und zu daraus resultierenden Fehlbildungen der Gefäße. Drittens, eine vorübergehende Beeinträchtigung der Pumpfunktion des Herzens im Entwicklungsstadium HH17 kann zu Bildung eines Ventrikelseptumsdefekts führen. Diese Ergebnisse tragen grundlegend dazu bei die Mechanismen die für die Formation und den Umbau der Pharyngealbogenarterien verantwortlich sind und jene für die Entstehung von Herz und Gefäß -Malformationen zu verstehen.Hereditary cardiovascular defects affect the heart and the great intrathoracic arteries. I hypothesized that abnormal heart morphogenesis results in abnormal hemodynamics in the developing pharyngeal arch arteries (PAA) and thereby induces vessel malformations. Biomechanical rather than genetic factors are thus responsible for the abnormal vessel configuration. My thesis aimed at testing this hypothesis by using the chick model. I designed and evaluated a procedure for manipulating the heart of early chick embryos of developmental stage 17 (Hamburger Hamilton, HH). The procedure caused a transitory defect in the compact myocardial layer of the presumptive right ventricle and induced transitory weakness of its pumping function and an aberrant trabeculated layer. Evaluations proofed that the manipulation targeted only the ventricle myocardium and left all other organs unharmed. At HH34 manipulated embryos showed serious heart defects, including ectopia cordis, ventricular septal defect (VSD) and double outlet right ventricle (DORV). All embryos showed also malformations of the great intrathoracic arteries. The results lead to following conclusions: Firstly, defects of the right ventricle and outflow tract are a possible reason for malformations of the great intrathoracic arteries. Secondly, abnormal hemodynamics in the pharyngeal arch artery system during its development can induce abnormal remodeling and malformations. Thirdly, transitory defective pumping function of the right ventricle at HH17 can induce a ventricular septal defect. The results significantly contribute to a better understanding of the mechanisms responsible for the formation and remodeling of the PAA system and the genesis of malformations of the heart and great intrathoracic arteries.submitted by Mag. rer. nat. Barbara Maurer-GesekZusammenfassung in deutscher SpracheMedizinische Universität Wien, Dissertation, 2016OeB

Visualising the Cardiovascular System of Embryos of Biomedical Model Organisms with High Resolution Episcopic Microscopy (HREM)

The article will briefly introduce the high-resolution episcopic microscopy (HREM) technique and will focus on its potential for researching cardiovascular development and remodelling in embryos of biomedical model organisms. It will demonstrate the capacity of HREM for analysing the cardiovascular system of normally developed and genetically or experimentally malformed zebrafish, frog, chick and mouse embryos in the context of the whole specimen and will exemplarily show the possibilities HREM offers for comprehensive visualisation of the vasculature of adult human skin. Finally, it will provide examples of the successful application of HREM for identifying cardiovascular malformations in genetically altered mouse embryos produced in the deciphering the mechanisms of developmental disorders (DMDD) program

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.IB is funded by Wellcome (WT206194). ATH and SE are the recipients of a Wellcome Trust Senior Investigator award and ATH is employed as a core member of staff within the NIHR funded Exeter Clinical Research Facility and is an NIHR senior investigator. EDF was a Naomi Berrie Fellow in Diabetes Research during the study. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number: 105636/Z/14/Z). CCW holds a Wellcome Trust Intermediate Clinical Fellowship (Grant Number: 105914/Z/14/Z). HH is funded by the Research Foundation-Flanders (FWO), the VUB Research Council and Stichting Diabetes Onderzoek Nederland