Search

Introduction: The labyrinthine zone of the placenta is where exchange of nutrients and waste occurs between maternal and fetal circulations. Proper development of the placental labyrinth is essential for successful growth of the developing fetus and abnormalities in placental development are associated with intrauterine growth restriction (IUGR), preeclampsia and fetal demise. Our previous studies demonstrate that Hectd1 is essential for development of the junctional and labyrinthine zones of the placenta. Here we further characterize labyrinthine zone defects in the Hectd1 mutant placenta.Methods: The structure of the mutant placenta was compared to wildtype littermates using histological methods. The expression of cell type specific markers was examined by immunohistochemistry and in situ hybridization.Results: Hectd1 is expressed in the labyrinthine zone throughout development and the protein is enriched in syncytiotrophoblast layer type I cells (SynT-I) and Sinusoidal Trophoblast Giant cells (S-TGCs) in the mature placenta. Mutation of Hectd1 results in pale placentas with frequent hemorrhages along with gross abnormalities in the structure of the labyrinthine zone including a smaller overall volume and a poorly elaborated fetal vasculature that contain fewer fetal blood cells. Examination of molecular markers of labyrinthine trophoblast cell types reveals increased Dlx3 positive cells and Syna positive SynT-I cells, along with decreased Hand1 and Ctsq positive sinusoidal trophoblast giant cells (S-TGCs).Discussion: Together these defects indicate that Hectd1 is required for development of the labyrinthine zonethe mouse placenta. [ABSTRACT FROM AUTHOR]

Abstract: Neural tube defects (NTDs) are among the most common structural birth defects observed in humans. Mouse models provide an excellent experimental system to study the underlying causes of NTDs. These models not only allow for identification of the genes required for neurulation, they provide tractable systems for uncovering the developmental, pathological and molecular mechanisms underlying NTDs. In addition, mouse models are essential for elucidating the mechanisms of gene–environment and gene–gene interactions that contribute to the multifactorial inheritance of NTDs. In some cases these studies have led to development of approaches to prevent NTDs and provide an understanding of the underlying molecular mechanism of these therapies prevent NTDs. [Copyright &y& Elsevier]

Abstract: This review presents an analysis of current research aimed at deciphering the interplay of cell extrinsic and intrinsic signals required for specification and differentiation of noradrenergic sympathetic ganglion neurons. The development of noradrenergic sympathetic ganglion neurons depends upon expression of a core set of DNA regulatory molecules, including the Phox2 homeodomain proteins and the basic helix–loop–helix proteins, HAND2 and MASH1 whose expression is dependent upon cell extrinsic cues. Both bone morphogenetic protein(s) and cAMP have an integral role in the specification/differentiation of noradrenergic sympathetic ganglion neurons but how signaling downstream of these molecules is integrated and identification of their particular functions is just beginning to be elucidated. Data currently available suggests a model with BMP providing both instructive and permissive cues in a pathway integrated by cAMP and MAPK by activation of both canonical and non-canonical intracellular signaling cascades. [Copyright &y& Elsevier]

The adenomatous polyposis coli (APC) protein functions as a negative regulator of the Wnt signaling pathway. In this capacity, APC forms a "destruction complex" with Axin, CK1α, and GSK3β to foster phosphorylation of the Wnt effectorβ-catenin earmarking it for Lys-48-linked polyubiquitylation and proteasomal degradation. APC is conjugated with Lys-63-linked ubiquitin chains when it is bound to Axin, but it is unclear whether this modification promotes the APC-Axin interaction or confers upon APC an alternative function in the destruction complex. Here we identify HectD1 as a candidate E3 ubiquitin ligase that modifies APC with Lys-63 polyubiquitin. Knockdown of HectD1 diminished APC ubiquitylation, disrupted the APCAxin interaction, and augmented Wnt3a-induced β-catenin stabilization and signaling. These results indicate that HectD1 promotes the APC-Axin interaction to negatively regulate Wnt signaling. [ABSTRACT FROM AUTHOR]