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Biomedical subjects

Xi He

Publications and source records attributed to Xi He.

At least 37 records · Page 2Linked to original sources
PubMed2005

SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.

Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST. Sclerosteosis shares remarkable similarities with "high bone mass" diseases caused by "gain-of-function" mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins. We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. Our findings suggest that SOST is an antagonist for Wnt signaling and that the loss of SOST function likely leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients.

Adaptor Proteins, Signal Transducing↗
PubMed2005

The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment.

Development of immature T-cell precursors (thymocytes) to either the CD4 helper or CD8 killer T-cell lineages correlates precisely with their T-cell receptor specificity for major histocompatibility complex class II or class I molecules, respectively, indicating that the process is carefully regulated. Although intensively studied owing to its importance in determining the composition of the mature T-cell compartment and as a general model of binary lineage decisions, the underlying molecular pathways remain obscure. We have previously reported a spontaneous mouse mutant (HD (helper deficient) mice) in which lineage commitment is specifically perturbed without affecting positive selection. Here we show that a point mutation in the zinc finger transcription factor Th-POK (T-helper-inducing POZ/Krüppel-like factor) is responsible for redirection of class-II-restricted thymocytes to the CD8 lineage in HD mice. Furthermore, we demonstrate that constitutive expression of this factor during thymic development leads to redirection of class-I-restricted thymocytes to the CD4 lineage, indicating that Th-POK is a master regulator of lineage commitment.

Amino Acid Sequence↗
PubMed2005

Antagonizing Wnt and FGF receptors: an enemy from within (the ER).

In this issue of Cell, Yamamoto et al. (2005) describe a novel molecule, Shisa, which functions in the endoplastic reticulum (ER) to prevent maturation of Frizzled (Fz) serpentine receptors and fibroblast growth factor receptor (FGFR). Shisa thus antagonizes Wnt and FGF signaling cell-autonomously, thereby promoting anterior patterning in Xenopus.

Animals↗
PubMed2005

CD4-CD8 lineage commitment: an inside view.

The mechanism of CD4-CD8 lineage commitment, which ensures the correlation between T cell receptor specificity and adoption of the T killer or T helper phenotype, has long been the subject of intense debate. Various approaches are slowly elucidating the underlying molecular pathways. Analysis of the function of T cell receptor signaling (the 'top-down' approach) supports the view that differences in signal strength and/or duration 'instruct' alternative commitment. Analysis of the transcriptional regulation of the genes encoding CD4 and CD8 (the 'bottom-up' approach) has identified critical cis-acting elements and their interacting factors. Finally, identification of the transcription factor Th-POK as a central component of the CD4 lineage-determining pathway has provided a new starting point from which to unravel this intriguing process 'from the inside out'.

Animals↗
PubMed2004

LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution.

The Wnt signaling pathway plays key roles in both embryogenesis and tumorigenesis. The low-density lipoprotein (LDL) receptor-related protein-6 (LRP6), a novel member of the expanding LDL receptor family, functions as an indispensable co-receptor for the Wnt signaling pathway. Although the role of LRP6 in embryonic development is now well established, its role in tumorigenesis is unclear. We report that LRP6 is readily expressed at the transcript level in several human cancer cell lines and human malignant tissues. Furthermore, using a retroviral gene transfer system, we find that stable expression of LRP6 in human fibrosarcoma HT1080 cells alters subcellular beta-catenin distribution such that the cytosolic beta-catenin level is significantly increased. This is accompanied by a significant increase in Wnt/beta-catenin signaling and cell proliferation. Finally, we demonstrate that LRP6 expression promotes tumorigenesis in vivo. These results thus indicate that LRP6 may function as a potential oncogenic protein by modulating Wnt/beta-catenin signaling.

Animals↗
PubMed2004

BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Adenomatous Polyposis Coli↗
PubMed2004

Wnt signaling went derailed again: a new track via the LIN-18 receptor?

In this issue of Cell, Inoue et al. (2004) reports that LIN-18, an atypical receptor tyrosine kinase related to mammalian Ryk and Drosophila Derailed, mediates Wnt signaling in parallel to LIN-17/Frizzled (Fz) during worm vulval development. LIN-18/Ryk and LIN-17/Fz appear to exhibit distinct Wnt specificity, and surprisingly, the LIN-18 intracellular domain may be dispensable.

Animals↗
PubMed2004

Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release.

Release of cytochrome c from the mitochondrial intermembrane space is critical to apoptosis induced by a variety of death stimuli. Bid is a BH3-only prodeath Bcl-2 family protein that can potently activate this efflux. In the current study, we investigated the mitochondrial localization of Bid and its interactions with mitochondrial phospholipids, focusing on their relationships with Bid-induced cytochrome c release. We found that Bid binding to the mitochondria required only three of its eight helical structures (alpha4-alpha6), but not the BH3 domain, and the binding could not be inhibited by the antideath molecule Bcl-x(L). Membrane fractionations indicated that tBid bound to mitochondrial outer membranes at both contact and noncontact sites. Bid could interact with specific cardiolipin species on intact mitochondria as identified by mass spectrometry. Like the binding to the mitochondria, this interaction could not be blocked by the mutation in the BH3 domain or by Bcl-x(L.) However, a cardiolipin-specific dye, 10-N-nonyl acridine orange, could preferentially suppress Bid binding to the mitochondrial contact site and inhibit Bid-induced mitochondrial cristae reorganization and cytochrome c release. These findings thus suggest that interactions of Bid with mitochondrial cardiolipin at the contact site can contribute significantly to its functions.

Aminoacridines↗
PubMed2004

Ozz; a new name on the long list of beta-catenin's nemeses.

In the February issue of Developmental Cell, Nastasi et al. describe Ozz, a muscle-specific ubiquitin ligase adaptor that regulates myofibril organization. Ozz appears to function in ubiquitination and degradation of membrane-bound, but not cytosolic, beta-catenin, whose turnover may be required for alignment and growth of the sarcomere, the basic contractile unit of myofibers.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

A mechanism for Wnt coreceptor activation.

LDL receptor related proteins 5 and 6 (LRP5/6) and their Drosophila homolog Arrow are single-span transmembrane proteins essential for Wnt/beta-catenin signaling, likely via acting as Wnt coreceptors. How Wnt activates LRP5/6/Arrow to initiate signal transduction is not well defined. Here we show that a PPPSP motif, which is reiterated five times in the LRP5/6/Arrow intracellular domain, is necessary and sufficient to trigger Wnt/beta-catenin signaling. A single PPPSP motif, upon transfer to the LDL receptor, fully activates the Wnt pathway, inducing complete axis duplication in Xenopus and TCF/beta-catenin-responsive transcription in human cells. We further show that Wnt signal-ing stimulates, and requires, phosphorylation of the PPPSP motif, which creates an inducible docking site for Axin, a scaffolding protein controlling beta-catenin stability. Our study identifies a critical signaling module and a key phosphorylation-dependent activation step of the Wnt receptor complex and reveals a unifying logic for transmembrane signaling by Wnts, growth factors, and cytokines.

Alanine↗
PubMed2004

Identification and comparative expression analyses of Daam genes in mouse and Xenopus.

During vertebrate embryogenesis, secreted Wnt molecules regulate cell fates by signaling through the canonical pathway mediated by beta-catenin, and regulate planar cell polarity (PCP) and convergent extension movements through alternative pathways. The phosphoprotein Dishevelled (Dsh/Dvl) is a Wnt signal transducer thought to function in all Wnt signaling pathways. A recently identified member of the Formin family, Daam (Dishevelled--associated activator of morphogenesis), regulates the morphogenetic movements of vertebrate gastrulation in a Wnt-dependent manner through direct interactions with Dsh/Dvl and RhoA. We describe two mouse Daam cDNAs, mDaam1 and mDaam2, which encode proteins characterized by highly conserved formin homology domains and which are expressed in complementary patterns during mouse development. Cross-species comparisons indicate that the expression domains of Xenopus Daam1 (XDaam1) mirror mDaam1 expression. Our results demonstrate that Daams are expressed in tissues known to require Wnts and are consistent with Daams being effectors of Wnt signaling during vertebrate development.

Adaptor Proteins, Signal Transducing↗
PubMed2004

LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.

Wnt signaling through the canonical beta-catenin pathway plays essential roles in development and disease. Low-density-lipoprotein receptor-related proteins 5 and 6 (Lrp5 and Lrp6) in vertebrates, and their Drosophila ortholog Arrow, are single-span transmembrane proteins that are indispensable for Wnt/beta-catenin signaling, and are likely to act as Wnt co-receptors. This review highlights recent progress and unresolved issues in understanding the function and regulation of Arrow/Lrp5/Lrp6 in Wnt signaling. We discuss Arrow/Lrp5/Lrp6 interactions with Wnt and the Frizzled family of Wnt receptors, and with the intracellular beta-catenin degradation apparatus. We also discuss the regulation of Lrp5/Lrp6 by other extracellular ligands, and LRP5 mutations associated with familial osteoporosis and other disorders.

Animals↗
PubMed2003

Identification of the haematopoietic stem cell niche and control of the niche size.

Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche'--the in vivo regulatory microenvironment where HSCs reside--and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+CD45- osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and beta-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.

Animals↗
PubMed2003

Predicting demographic group structures based on DNA sequence data.

The ability to infer relationships between groups of sequences, either by searching for their evolutionary history or by comparing their sequence similarity, can be a crucial step in hypothesis testing. Interpreting relationships of human immunodeficiency virus type 1 (HIV-1) sequences can be challenging because of their rapidly evolving genomes, but it may also lead to a better understanding of the underlying biology. Several studies have focused on the evolution of HIV-1, but there is little information to link sequence similarities and evolutionary histories of HIV-1 to the epidemiological information of the infected individual. Our goal was to correlate patterns of HIV-1 genetic diversity with epidemiological information, including risk and demographic factors. These correlations were then used to predict epidemiological information through analyzing short stretches of HIV-1 sequence. Using standard phylogenetic and phenetic techniques on 100 HIV-1 subtype B sequences, we were able to show some correlation between the viral sequences and the geographic area of infection and the risk of men who engage in sex with men. To help identify more subtle relationships between the viral sequences, the method of multidimensional scaling (MDS) was performed. That method identified statistically significant correlations between the viral sequences and the risk factors of men who engage in sex with men and individuals who engage in sex with injection drug users or use injection drugs themselves. Using tree construction, MDS, and newly developed likelihood assignment methods on the original 100 samples we sequenced, and also on a set of blinded samples, we were able to predict demographic/risk group membership at a rate statistically better than by chance alone. Such methods may make it possible to identify viral variants belonging to specific demographic groups by examining only a small portion of the HIV-1 genome. Such predictions of demographic epidemiology based on sequence information may become valuable in assigning different treatment regimens to infected individuals.

Adolescent↗
PubMed2003

Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation.

Wnt/Frizzled (Fz) signaling controls cell polarity/movements during vertebrate gastrulation via incompletely defined mechanisms. We demonstrated previously that Wnt/Fz activation of Rho, a GTPase and regulator of cytoskeletal architecture, is essential for vertebrate gastrulation. Here we report that in mammalian cells and Xenopus embryos, Wnt/Fz signaling coactivates Rho and Rac, another GTPase and distinct regulator of cytoskeletal architecture. Wnt/Fz activation of Rac is independent of Rho and mediates Wnt/Fz activation of Jun N-terminal kinase (JNK). Dishevelled (Dvl), a cytoplasmic protein downstream of Fz, forms a Wnt-induced complex with Rac independent of the Wnt-induced Dvl-Rho complex. Depletion or inhibition of Rac function perturbs Xenopus gastrulation without affecting Wnt/Fz activation of the Rho or beta-catenin pathway. We propose that parallel activation of Rac and Rho pathways by Wnt/Fz signaling is required for cell polarity and movements during vertebrate gastrulation.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Distinct strategies to make nucleosomal DNA accessible.

One hallmark of ATP-dependent remodeling complexes is the ability to make nucleosomal DNA accessible to regulatory factors. We have compared two prominent human ATP-dependent remodelers, BRG1 from the SWI/SNF family and SNF2h from the ISWI family, for their abilities to make a spectrum of nucleosomal sites accessible. By measuring rates of remodeling at seven different sites on a mononucleosome and at six different sites on the central nucleosome of a trinucleosome, we have found that BRG1 opens centrally located sites more than an order of magnitude better than SNF2h. We provide evidence that this capability of BRG1 is caused by its ability to create DNA loops on the surface of a nucleosome, even when that nucleosome is constrained by adjacent nucleosomes. This specialized ability to make central sites accessible should allow SWI/SNF family complexes to facilitate binding of nuclear factors in chromatin environments where adjacent nucleosomes might otherwise constrain mobility.

Adenosine Triphosphate↗
PubMed2003

A Wnt-Wnt situation.

A recent Juan March Foundation workshop on "wnt genes and Wnt signaling" brought developmental and cancer biologists together to share some of the latest advances in Wnt research. Discussion topics included molecular, genetic, and genomic dissections of wnt genes in embryogenesis and cancer, Wnt signaling components and downstream targets, interactions with other signaling pathways, cell biological aspects of Wnt signaling, and a first glimpse of a purified Wnt protein.

Animals↗