DOCSLIB.ORG

<I>BOC</I> Is a Modifier Gene in Holoprosencephaly

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
<I>BOC</I> Is a Modifier Gene in Holoprosencephaly Received: 12 May 2017 Revised: 20 June 2017 Accepted: 28 June 2017 DOI: 10.1002/humu.23286 BRIEF REPORT BOC is a modifier gene in holoprosencephaly Mingi Hong1∗ Kshitij Srivastava2∗ Sungjin Kim1 Benjamin L. Allen3 Daniel J. Leahy4 Ping Hu2 Erich Roessler2 Robert S. Krauss1† Maximilian Muenke2† 1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 2Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 3Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 4Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas Correspondence Robert S. Krauss (for editorial communication), Abstract Department of Cell, Developmental and Regen- Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a erative Biology, Icahn School of Medicine at complex etiology. Heterozygous, loss-of-function mutations in the sonic hedgehog (SHH) pathway Mount Sinai, New York, New York 10029. Email: [email protected] are associated with HPE. However, mutation carriers display highly variable clinical presentation, Maximilian Muenke, Medical Genetics Branch, leading to an “autosomal dominant with modifier” model, in which the penetrance and expressiv- National Human Genome Research Institute, ity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers National Institutes of Health, Bethesda, Mary- land 20892. have not been identified. Boc encodes a SHH coreceptor and is a silent HPE modifier gene in mice. Email: [email protected] Here, we report the identification of missense BOC variants in HPE patients. Consistent with these ∗Mingi Hong and Kshitij Srivastava contributed alleles functioning as HPE modifiers, individual variant BOC proteins had either loss- or gain-of- equally to this work. function properties in cell-based SHH signaling assays. Therefore, in addition to heterozygous † Robert S. Krauss and Maximilian Muenke con- loss-of-function mutations in specific SHH pathway genes and an ill-defined environmental com- tributed equally to this work as senior authors. ponent, our findings identify a third variable in HPE: low-frequency modifier genes, BOC being the Contract grant sponsors: NIH (DE024748, GM118751, CA198074); Cancer Prevention first identified. and Research Institute of Texas (CPRIT) (award RR160023); Division of Intramural Research, KEYWORDS NHGRI, NIH. birth defect, BOC, gene variant, holoprosencephaly, modifier gene, sonic hedgehog Communicated by Hildegard Kehrer-Sawatzki Many structural birth defects are thought to arise from a complex com- nature. While bona fide pathogenic mutations in SHH and other genes bination of genetic and environmental risk factors (Krauss & Hong associated with HPE continue to be cataloged, identification of poten- 2016). Holoprosencephaly (HPE; MIM# 236100), a common and often tial HPE modifiers is in its infancy. devastating defect in midline patterning of the forebrain and mid- The binding of SHH to its primary cell surface receptor PTCH1 face, is a prototypical example. HPE encompasses a phenotypic spec- (MIM# 601309) initiates a signaling cascade to modulate GLI tran- trum that ranges from failure to partition the forebrain into hemi- scription factors, which induce expression of pathway target genes spheres and cyclopia, to mild midfacial anomalies that occur with- (Lee et al., 2016). Among the direct target genes is GLI1 (MIM# out forebrain involvement (Geng & Oliver, 2009). Heterozygous, loss- 165220) itself. SHH and PTCH1 both bind to several coreceptors, of-function mutations in components of the sonic hedgehog (SHH; including CDON (MIM# 608707), BOC (MIM# 608708), and GAS1 MIM# 600725) signaling pathway are frequently associated with HPE (MIM# 139185) (Bae et al., 2011; Izzi et al., 2011; Tenzen et al., 2006). (Roessler & Muenke, 2010). However, highly variable clinical presenta- Studies with knockout mice revealed that these three coreceptors have tion is seen in mutation carriers, even within pedigrees. Furthermore, overlapping and partially redundant function in supporting SHH sig- in many “sporadic” cases, mutations in SHH are inherited from a par- naling during development; embryos lacking all three have a nearly ent with little or no clinical manifestation (Solomon et al., 2012). Sta- complete loss of pathway activity (Allen et al., 2011). Heterozygous, tistical analyses have led to an “autosomal dominant with modifier” loss-of-function mutations in CDON and GAS1 have been identified in model, in which the penetrance and expressivity of a predisposing het- HPE patients (Bae et al., 2011; Pineda-Alvarez et al., 2012; Ribeiro, erozygous mutation is graded by modifiers (Roessler, Vélez, Zhou, & Quiezi, Nascimento, Bertolacini, & Richieri-Costa, 2010). Consistent Muenke, 2012). Such modifiers may be genetic or environmental in with these observations, mice with targeted mutations in either Cdon Human Mutation. 2017;38:1464–1470. wileyonlinelibrary.com/journal/humu c 2017 Wiley Periodicals, Inc. 1464 HONG ET AL. 1465 or Gas1 display a range of HPE phenotypes (Allen, Tenzen, & McMa- vectors encoding four of the HPE-associated BOC variants: hon, 2007; Hong & Krauss, 2012; Martinelli & Fan, 2007; Seppala et al., p.Arg533Leu, p.Gly556Glu, p.Arg697Pro, and p.Pro828Arg. The 2007; Zhang, Kang, Cole, Yi, & Krauss, 2006). In contrast, mice lacking p.Arg533Leu and p.Gly556Glu substitutions are in Fn3 repeat 1, Boc do not have HPE (Zhang, Hong, Bae, Kang, & Krauss, 2011). How- p.Arg697Pro is in the linker region between Fn3 repeats 1 and 2, and ever, genetic removal of Boc from Cdon−/− or Gas1−/− mice exacerbates p.Pro828Arg is in the linker region between Fn3 repeat 3 and the their HPE phenotype (Seppala, Xavier, Fan, & Cobourne, 2014; Zhang transmembrane region. These variants were selected because: (1) they et al., 2011). Therefore, Boc functions as a silent HPE modifier gene in were located in the Fn repeat region of BOC, which is critical for Shh mice. Here, we address the potential role of BOC in HPE pathogenesis signaling (Song, Holtz, Pinskey, & Allen, 2015); and (2) they resemble in humans. similarly located, HPE-associated, loss-of-function, missense muta- We performed high-throughput screening of BOC (NM_033254.3) tions in CDON in that they were highly nonconservative substitutions for 360 HPE patients using high-resolution melting, as described (Kau- in evolutionarily conserved residues (Bae et al., 2011). Prioritization of var et al., 2011). Additionally, 384 unrelated individuals were screened these variants was not based on either retrospective allele frequency as controls. HPE and control samples with melting profiles that devi- or ANNOVAR annotation criteria, which were not available at the time ated from wild-type melting curves were directly sequenced for vari- of study design. ant confirmation. A total of eight different amino acid substitution Each variant was expressed at easily detectable levels when tran- variants in BOC were identified in HPE patients, including one that siently transfected in HEK293T cells (Fig. 1B). When expressed in TKO was found in two unrelated patients and two that were present in a cells subsequently treated with SHH, the p.Arg533Leu, p.Arg697Pro, single patient (Table 1). There are over 400 BOC missense variants and p.Pro828Arg variants were similar to wild-type BOC in having reported in ExAC. We note that most of the variants we identified are little ability to promote ligand-dependent Gli1 expression (Fig. 1C). rare (Table 1), including p.Gly556Glu, which has not been previously Surprisingly, the p.Gly556Glu variant had substantial activity in this reported. An exception is p.Pro828Arg, which has a minor allele fre- assay, conferring on BOC the ability to promote SHH signaling. There- quency of 0.0017, more common than the ∼1:10,000 birth frequency fore, p.Gly556Glu is a ligand-dependent, gain-of-function mutant. When of HPE (Leoncini et al., 2008), and consistent with possible function as lysates of cells expressing wild-type BOC or the HPE-associated vari- a modifier allele. All individuals were also studied for the four genes ants were analyzed by Western blotting after conditions of limited pro- most commonly screened in HPE (SHH, ZIC2 (MIM# 603073), SIX3 teolysis, p.Gly556Glu did not produce a product formed by the others (MIM# 603714), and TGIF (MIM# 602630)). One patient had a trun- (Fig. 1D). This result suggests that p.Gly556Glu may have an altered cating mutation in ZIC2, and another patient had a deletion of TGIF conformation that contributes to its gain of function. A similar obser- (Table 1). vation was made for some of the HPE-associated CDON variants that To explore the functional consequences of HPE-associated BOC displayed a loss of function (Bae et al., 2011). variants, we developed a cell-based assay for BOC activity. Exogenous The ability of p.Gly556Glu to confer SHH-dependent Gli1 expres- expression of BOC had little ability to enhance SHH signaling in wild- sion to TKO cells offered an opportunity to assess whether the type mouse embryo fibroblasts (MEFs) or even Cdon−/−;Boc−/− MEFs other three HPE-associated variants might have the anticipated (not shown). To work in as sensitive a cell system as possible, we used loss-of-function property by constructing BOC expression vectors Cdon−/−;Boc−/−;Gas1−/− MEFs (TKO cells) (Mathew et al., 2014). When that harbor the p.Gly556Glu change along with, independently,
Load more

Recommended publications
  • Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ARTICLE Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors Gyu-Un Bae,1,2,4,6 Sabina Domene´,3,4,7 Erich Roessler,3 Karen Schachter,1,8 Jong-Sun Kang,2,5,* Maximilian Muenke,3,5,* and Robert S. Krauss1,5 Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOC, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON’s ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE.
    [Show full text]
  • "The Genecards Suite: from Gene Data Mining to Disease Genome Sequence Analyses". In: Current Protocols in Bioinformat
    The GeneCards Suite: From Gene Data UNIT 1.30 Mining to Disease Genome Sequence Analyses Gil Stelzer,1,5 Naomi Rosen,1,5 Inbar Plaschkes,1,2 Shahar Zimmerman,1 Michal Twik,1 Simon Fishilevich,1 Tsippi Iny Stein,1 Ron Nudel,1 Iris Lieder,2 Yaron Mazor,2 Sergey Kaplan,2 Dvir Dahary,2,4 David Warshawsky,3 Yaron Guan-Golan,3 Asher Kohn,3 Noa Rappaport,1 Marilyn Safran,1 and Doron Lancet1,6 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 2LifeMap Sciences Ltd., Tel Aviv, Israel 3LifeMap Sciences Inc., Marshfield, Massachusetts 4Toldot Genetics Ltd., Hod Hasharon, Israel 5These authors contributed equally to the paper 6Corresponding author GeneCards, the human gene compendium, enables researchers to effectively navigate and inter-relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better-targeted data queries, and friendlier user experience. It also provides a stronger foundation for the GeneCards suite of companion databases and analysis tools. Improved data unification includes gene-disease links via MalaCards and merged biological pathways via PathCards, as well as drug information and proteome expression. VarElect, another suite member, is a phenotype prioritizer for next-generation sequencing, leveraging the GeneCards and MalaCards knowledgebase. It au- tomatically infers direct and indirect scored associations between hundreds or even thousands of variant-containing genes and disease phenotype terms. Var- Elect’s capabilities, either independently or within TGex, our comprehensive variant analysis pipeline, help prepare for the challenge of clinical projects that involve thousands of exome/genome NGS analyses.
    [Show full text]
  • Duke University Dissertation Template
    Gene-Environment Interactions in Cardiovascular Disease by Cavin Keith Ward-Caviness Graduate Program in Computational Biology and Bioinformatics Duke University Date:_______________________ Approved: ___________________________ Elizabeth R. Hauser, Supervisor ___________________________ William E. Kraus ___________________________ Sayan Mukherjee ___________________________ H. Frederik Nijhout Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Program in Computational Biology and Bioinformatics in the Graduate School of Duke University 2014 i v ABSTRACT Gene-Environment Interactions in Cardiovascular Disease by Cavin Keith Ward-Caviness Graduate Program in Computational Biology and Bioinformatics Duke University Date:_______________________ Approved: ___________________________ Elizabeth R. Hauser, Supervisor ___________________________ William E. Kraus ___________________________ Sayan Mukherjee ___________________________ H. Frederik Nijhout An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Program in Computational Biology and Bioinformatics in the Graduate School of Duke University 2014 Copyright by Cavin Keith Ward-Caviness 2014 Abstract In this manuscript I seek to demonstrate the importance of gene-environment interactions in cardiovascular disease. This manuscript contains five studies each of which contributes to our understanding of the joint impact of genetic variation
    [Show full text]
  • Cdon Acts As a Hedgehog Decoy Receptor During Proximal-Distal Patterning of the Optic Vesicle
    ARTICLE Received 10 Dec 2013 | Accepted 26 May 2014 | Published 8 Jul 2014 DOI: 10.1038/ncomms5272 OPEN Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle Marcos Julia´n Cardozo1,2, Luisa Sa´nchez-Arrones1,2,A´frica Sandonis1,2, Cristina Sa´nchez-Camacho2,w, Gaia Gestri3, Stephen W. Wilson3, Isabel Guerrero1 & Paola Bovolenta1,2 Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes stalk specification. In the absence of Hh signalling, the stalks are not specified, causing cyclopia. Recent studies showed that the cell adhesion molecule Cdon forms a heteromeric complex with the Hh receptor Patched 1 (Ptc1). This receptor complex binds Hh and enhances signalling activation, indicating that Cdon positively regulates the pathway. Here we show that in the developing zebrafish and chick optic vesicle, in which cdon and ptc1 are expressed with a complementary pattern, Cdon acts as a negative Hh signalling regulator. Cdon predominantly localizes to the basolateral side of neuroepithelial cells, promotes the enlargement of the neuroepithelial basal end-foot and traps Hh protein, thereby limiting its dispersion. This Ptc-independent function protects the retinal primordium from Hh activity, defines the stalk/retina boundary and thus the correct proximo-distal patterning of the eye. 1 Centro de Biologı´a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı´ficas—Universidad Auto´noma de Madrid, 28049 Madrid Spain. 2 Ciber de Enfermedades Raras (CIBERER), ISCIII, c/ Nicolas Cabrera 1, 28049 Madrid Spain. 3 Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
    [Show full text]
  • Hedgehog Pathway-Regulated Gene Networks in Cerebellum Development and Tumorigenesis
    Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis Eunice Y. Leea, Hongkai Jib, Zhengqing Ouyangc, Baiyu Zhoud, Wenxiu Mae, Steven A. Vokesf, Andrew P. McMahong, Wing H. Wongd, and Matthew P. Scotta,1 aDepartments of Developmental Biology, Genetics, and Bioengineering, Howard Hughes Medical Institute, and Departments of cBiology, dStatistics and Health Research and Policy, and eComputer Science, Stanford University, Stanford, CA 94305; bDepartment of Biostatistics, Johns Hopkins University, Baltimore, MD, 21205; fSection of Molecular Cell and Development Biology, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712; and gDepartment of Molecular and Cellular Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 Contributed by Matthew P. Scott, April 20, 2010 (sent for review November 24, 2009) Many genes initially identified for their roles in cell fate determi- genes influence murine MB development (18–21), so at least nation or signaling during development can have a significant part of the Shh-stimulated transcriptional program in GNPs is impact on tumorigenesis. In the developing cerebellum, Sonic active and functional during carcinogenesis. Genome-wide ex- hedgehog (Shh) stimulates the proliferation of granule neuron pression profiling has been widely used to understand the tran- precursor cells (GNPs) by activating the Gli transcription factors. scriptional effects of Shh signaling, but it does not distinguish Inappropriate activation of Shh target genes results in unrestrained direct and indirect effects. Many questions remain regarding the cell division and eventually medulloblastoma, the most common repertoire and regulation of Hh target genes and the extent of pediatric brain malignancy. We find dramatic differences in the their overlap in different tissues and cancers.
    [Show full text]
  • Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
    cells Review Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss 1, 1, 1 1,2,3 1 Gayle B. Collin y, Navdeep Gogna y, Bo Chang , Nattaya Damkham , Jai Pinkney , Lillian F. Hyde 1, Lisa Stone 1 , Jürgen K. Naggert 1 , Patsy M. Nishina 1,* and Mark P. Krebs 1,* 1 The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; [email protected] (G.B.C.); [email protected] (N.G.); [email protected] (B.C.); [email protected] (N.D.); [email protected] (J.P.); [email protected] (L.F.H.); [email protected] (L.S.); [email protected] (J.K.N.) 2 Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand 3 Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand * Correspondence: [email protected] (P.M.N.); [email protected] (M.P.K.); Tel.: +1-207-2886-383 (P.M.N.); +1-207-2886-000 (M.P.K.) These authors contributed equally to this work. y Received: 29 February 2020; Accepted: 7 April 2020; Published: 10 April 2020 Abstract: Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated.
    [Show full text]
  • The Cell Surface Membrane Proteins Cdo and Boc Are Components and Targets of the Hedgehog Signaling Pathway and Feedback Network in Mice
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Cell 10, 647–656, May, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.devcel.2006.04.004 The Cell Surface Membrane Proteins Cdo and Boc Are Components and Targets of the Hedgehog Signaling Pathway and Feedback Network in Mice Toyoaki Tenzen,1 Benjamin L. Allen,1 Francesca Cole,2 determining both the number and full range of ventral Jong-Sun Kang,2 Robert S. Krauss,2 cell types (reviewed in Ingham and McMahon, 2001). and Andrew P. McMahon1,* Patched-1 (Ptch1) encodes the vertebrate HH receptor 1 Department of Molecular and Cellular Biology while Hedgehog-interacting protein-1 (Hhip1) encodes Harvard University an unrelated membrane-associated protein that simi- 16 Divinity Avenue larly binds all mammalian HH ligands. Ptch1 and Hhip1 Cambridge, Massachusetts 02138 are upregulated in response to HH signaling; their feed- 2 Brookdale Department of Molecular, Cell, back functions serve to modify the range of signaling and Developmental Biology and regional response of target cells (Chuang and Box 1020 McMahon, 1999; Jeong and McMahon, 2005). A third Mount Sinai School of Medicine HH binding factor, Growth arrest-specific-1 (Gas1), is One Gustave L. Levy Place thought to inhibit Shh signaling; Gas1 is itself repressed New York, New York 10029 in response to HH signaling (Lee et al., 2001). Here we present evidence that Cdo and Boc, which encode cell surface bound members of the Ig/fibronectin domain Summary superfamily, are novel feedback components that act in a different manner, to enhance Shh signaling within Cdo and Boc encode cell surface Ig/fibronectin super- subregions of Shh’s neural target field.
    [Show full text]
  • BOC Is a Modifier Gene in Holoprosencephaly
    BOC is a Modifier Gene in Holoprosencephaly Mingi Hong1,5, Kshitij Srivastava2,5, Sungjin Kim1, Benjamin L. Allen3, Daniel J. Leahy4, Ping Hu2, Erich Roessler2, Robert S. Krauss1,6,7, and Maximilian Muenke2,6,7 1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 10029. 2Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA 20892. 3Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA, 48109. 4Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA, 78712. 5 Contributed equally to this work 6 Contributed equally as senior authors 7Authors for correspondence: Robert S. Krauss (for editorial communication), Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Phone: 212-241-2177; Fax: 212-860-9279 e-mail: [email protected] This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/humu.23286. This article is protected by copyright. All rights reserved. Maximilian Muenke, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. e-mail: [email protected] Grant sponsors: This work was supported by grants NIH DE024748, GM118751, CA198074; Cancer Prevention and Research Institute of Texas (CPRIT) award RR160023; and by the Division of Intramural Research, NHGRI, NIH.
    [Show full text]
  • Zebrafish Spinal Cord Oligodendrocyte Formation Requires Boc Function
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.31.429029; this version posted January 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Kearns et al., 01/29/2021 1 Zebrafish spinal cord oligodendrocyte formation requires boc 2 function 3 4 Christina A. Kearns. Macie Walker, Andrew M. Ravanellia, Kayt Scott, Madeline R. Arzbeckerb and Bruce 5 Appel1 6 7 Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus and Children’s 8 Hospital Colorado, Aurora, Colorado, 80045, USA 9 10 a current address: MilliporeSigma, 2909 Laclede Ave., St. Louis, MO, USA 11 b current address: University of Wisconsin School of Medicine and Public Health, 750 Highland Ave. Madison, WI 53726 12 1 Correspondence: Bruce Appel, MS 8108, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045; 303- 13 724-3465; [email protected] 14 15 Abstract 16 The axis of the vertebrate neural tube is patterned, in part, by a ventral to dorsal gradient of Shh signaling. In the ventral spinal 17 cord, Shh induces concentration-dependent expression of transcription factors, subdividing neural progenitors into distinct domains 18 that subsequently produce distinct neuronal and glial subtypes. In particular, progenitors of the pMN domain express the bHLH 19 transcription factor Olig2 and produce motor neurons followed by oligodendrocytes, the myelinating glial cell type of the central 20 nervous system.
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]
  • Pathway and Network Analysis for Mrna and Protein Profiling Data
    Pathway and network analysis for mRNA and protein profiling data Bing Zhang, Ph.D. Professor of Molecular and Human Genetics Lester & Sue Smith Breast Center Baylor College of Medicine [email protected] VU workshop, 2016 Gene expression DNA Transcription Transcriptome Transcriptome RNA mRNA decay profiling Translation Proteome Protein Proteome Protein degradation profiling Phenotype Networks VU workshop, 2016 Overall workflow of gene expression studies Biological question Experimental design Microarray RNA-Seq Shotgun proteomics Image analysis Reads mapping Peptide/protein ID Signal intensities Read counts Spectral counts; Intensities Data Analysis Experimental Hypothesis validation VU workshop, 2016 Data matrix Samples probe_set_id HNE0_1 HNE0_2 HNE0_3 HNE60_1 HNE60_2 HNE60_3 1007_s_at 8.6888 8.5025 8.5471 8.5412 8.5624 8.3073 1053_at 9.1558 9.1835 9.4294 9.2111 9.1204 9.2494 117_at 7.0700 7.0034 6.9047 9.0414 8.6382 9.2663 121_at 9.7174 9.7440 9.6120 9.7581 9.7422 9.7345 1255_g_at 4.2801 4.4669 4.2360 4.3700 4.4573 4.2979 1294_at 6.3556 6.2381 6.2053 6.4290 6.5074 6.2771 Genes 1316_at 6.5759 6.5330 6.4709 6.6636 6.6438 6.4688 1320_at 6.5497 6.5388 6.5410 6.6605 6.5987 6.7236 1405_i_at 4.3260 4.4640 4.1438 4.3462 4.3876 4.6849 1431_at 5.2191 5.2070 5.2657 5.2823 5.2522 5.1808 1438_at 7.0155 6.9359 6.9241 7.0248 7.0142 7.0971 1487_at 8.6361 8.4879 8.4498 8.4470 8.5311 8.4225 1494_f_at 7.3296 7.3901 7.0886 7.2648 7.6058 7.2949 1552256_a_at 10.6245 10.5235 10.6522 10.4205 10.2344 10.3144 1552257_a_at 10.3224 10.1749 10.1992 10.2464 10.2191
    [Show full text]
  • The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development
    bioRxiv preprint doi: https://doi.org/10.1101/2020.02.04.934497; this version posted February 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development Martha L. Echevarría-Andino1* and Benjamin L. Allen1* 1Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA *Correspondence: [email protected], [email protected] Key words: Hedgehog, GAS1, CDON, BOC, craniofacial development, holoprosencephaly Running title: BOC regulates HH signaling Summary statement Here we identify dual, tissue-specific roles for the Hedgehog co-receptor BOC in both the promotion and antagonism of Hedgehog signaling during craniofacial development. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.04.934497; this version posted February 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Abstract 2 The Hedgehog (HH) pathway controls multiple aspects of craniofacial development. HH ligands 3 signal through the canonical receptor PTCH1, and three co-receptors– GAS1, CDON and BOC. Together, 4 these co-receptors are required during embryogenesis to mediate proper HH signaling. Here we investigated 5 the individual and combined contributions of GAS1, CDON and BOC to HH-dependent mammalian 6 craniofacial development. Individual deletion of either Gas1 or Cdon results in variable holoprosencephaly 7 phenotypes, characterized by the failure to divide and form the telencephalon and midfacial structures.
    [Show full text]