Essentiality of Regulator of G Protein Signaling 6 and Oxidized Ca2+/Calmodulin‐Dependent Protein Kinase II in Notch Signaling and Cardiovascular Development

نویسندگان

  • Bandana Chakravarti
  • Jianqi Yang
  • Katelin E. Ahlers‐Dannen
  • Zili Luo
  • Heather A. Flaherty
  • David K. Meyerholz
  • Mark E. Anderson
  • Rory A. Fisher
چکیده

BACKGROUND Congenital heart defects are the most common birth defects worldwide. Although defective Notch signaling is the major cause of mouse embryonic death from cardiovascular defects, how Notch signaling is regulated during embryonic vasculogenesis and heart development is poorly understood. METHODS AND RESULTS Regulator of G protein signaling 6 (RGS6)-/-/Ca2+/calmodulin-dependent protein kinase II (CaMKII)VV double mutant mice were developed by crossing RGS6-/- mice with mice expressing an oxidation-resistant CaMKIIδ (CaMKIIVV), and the resulting embryonic defects/lethality were investigated using E7.5 to E15.5 embryos. While loss of either RGS6 or oxidized CaMKIIδ does not alter embryogenesis, their combined loss causes defective Notch signaling, severe cardiovascular defects, and embryonic lethality (≈E10.5-11.5). Embryos lacking RGS6 and expressing oxidation-resistant CaMKIIδ exhibit reduced myocardial wall thickness, abnormal trabeculation, and arterial specification defects. Double mutants show vascular remodeling defects, including reduced neurovascularization, delayed neural tube maturation, and small dorsal aortae. These striking cardiovascular defects were accompanied by placental and yolk sac defects in angiogenesis, hematopoiesis, and vascular remodeling similar to what is seen with defective Notch1 signaling. Double mutant hearts, embryos, and yolk sacs exhibit profound downregulation of Notch1, Jagged 1, and Notch downstream target genes Hey1, Hey2, and Hey1L as well as impaired Notch1 signaling in embryos/hearts. CONCLUSIONS RGS6 and oxidized CaMKIIδ together function as novel critical upstream modulators of Notch signaling required for normal cardiovascular development and embryo survival. Their combined need indicates that they function in parallel pathways needed for Notch1 signaling in yolk sac, placenta and embryos. Thus, dysregulated embryonic RGS6 expression and oxidative activation of CaMKII may potentially contribute to congenital heart defects.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

P26: Long-Term Potentiation: The Mechanisms of CaMKII in Lerarning and Memory

Long-term potentiation (LTP) is a form of activity dependent plasticity that induced by high-frequency stimulation or theta burst stimulation and results in synaptic transmission. Several Studies have been shown that LTP is one of the most important processes in the CNS that plays an important role in learning and memory formation. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major...

متن کامل

Activation of calcium/calmodulin-dependent kinase II following bovine rotavirus enterotoxin NSP4 expression

Objective(s): The rotavirus nonstructural protein 4 (NSP4) is responsible for the increase in cytoplasmic calcium concentration through a phospholipase C-dependent and phospholipase C-independent pathways in infected cells. It is shown that increasing of intracellular calcium concentration in rotavirus infected cells is associated with the activation of some members of protein kinases family su...

متن کامل

Changes in regulator of G protein signaling-4 gene expression in the spinal cord of adrenalectomized rats in response to intrathecal morphine

Introduction: Regulators of G-protein signaling protein negatively control G protein -coupled receptor signaling duration by accelerating Gα subunit guanosine triphosphate hydrolysis. Since regulator of G-protein signaling4 has an important role in modulating morphine effects at the cellular level and the exact mechanism(s) of adrenalectomy-induced morphine sensitization have not been fully cl...

متن کامل

Changes in expression of klotho affect physiological processes, diseases, and cancer

Klotho (KL) encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the KL gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of tar...

متن کامل

Effect of chronic morphine administration on Ca2+/Calmodulin-Dependent protein kinase IIα activity in rat locus coeruleus and its possible role in morphine dependency

Introduction: The aim of this study was to assess the effect of Ca2+/calmodulin-dependent kinase IIα (CaMKIIα) inhibitor (KN-93) injection into the locus coeruleus (LC) on the modulation of withdrawal signs. We also sought to study the effect of chronic morphine administration on CaMKIIα activity in the rat LC. Methods: The research was based on behavioral and molecular studies. In the behav...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2017