Boston Children's Hospital

About: Boston Children's Hospital is a healthcare organization based out in Boston, Massachusetts, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 165409 authors who have published 215589 publications receiving 6885627 citations.

A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.

Abstract: Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease1. The canonical Wnt/β-catenin pathway requires a single-span transmembrane receptor, low-density lipoprotein (LDL)-receptor-related protein 6 (LRP6)2,3,4, whose phosphorylation at multiple PPPSP motifs is induced upon stimulation by Wnt and is critical for signal transduction5. The kinase responsible for LRP6 phosphorylation has not been identified. Here we provide biochemical and genetic evidence for a ‘dual-kinase’ mechanism for LRP6 phosphorylation and activation. Glycogen synthase kinase 3 (GSK3), which is known for its inhibitory role in Wnt signalling through the promotion of β-catenin phosphorylation and degradation, mediates the phosphorylation and activation of LRP6. We show that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1, and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We show further that a membrane-associated form of GSK3, in contrast with cytosolic GSK3, stimulates Wnt signalling and Xenopus axis duplication. Our results identify two key kinases mediating Wnt co-receptor activation, reveal an unexpected and intricate logic of Wnt/β-catenin signalling, and illustrate GSK3 as a genuine switch that dictates both on and off states of a pivotal regulatory pathway.

Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants.

Abstract: The timing and synchronization of postnatal myelination in the human central nervous system (CNS) are complex. We found eight time-related patterns of CNS myelination during the first two postnatal years in autopsied infants. The intensity of myelination was graded in 162 infants with diverse diseases on an ordinal scale of degrees 0-4. The Ayer method for maximum likelihood estimates for censored data was utilized to generate curves of the temporal changes in the percent of infants with degrees 0 through 4 of myelin in 62 white matter sites. These sites fall into eight subgroups determined by the presence or absence of microscopic myelin (degree 1) at birth and the median age at which mature myelin (degree 3) is reached. There is variability in the timing of myelination within and across axonal systems, and early onset of myelination is not always followed by early myelin maturation. We reexamined general rules governing the timing of myelination proposed by previous investigators, and found that those rules are neither complete nor inviolate, and that there is a complex interplay among them. This study specifies distinct periods of maturation in which myelinating pathways are potentially vulnerable to insult during the first two postnatal years.

Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells

Abstract: Genes expressed in erythroid cells contain binding sites for a cell-specific factor believed to be an important regulator for this haematopoietic lineage. Using high-level transient expression in mammalian cells, we have identified complementary DNA encoding the murine protein. The factor, a new member of the zinc-finger family of DNA-binding proteins, is restricted to erythroid cells at the level of RNA expression and is closely homologous between mouse and man.

Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.

Abstract: Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. Crouzon syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.