Development of the Endochondral Skeleton
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Wnt Signalling During Limb Development
Int. J. Dev. Biol. 46: 927-936 (2002) Wnt signalling during limb development VICKI L. CHURCH and PHILIPPA FRANCIS-WEST* Department of Craniofacial Development, King’s College London, Guy’s Hospital, London, UK ABSTRACT Wnts control a number of processes during limb development - from initiating outgrowth and controlling patterning, to regulating cell differentiation in a number of tissues. Interactions of Wnt signalling pathway components with those of other signalling pathways have revealed new mechanisms of modulating Wnt signalling, which may explain how different responses to Wnt signalling are elicited in different cells. Given the number of Wnts that are expressed in the limb and their ability to induce differential responses, the challenge will be to dissect precisely how Wnt signalling is regulated and how it controls limb development at a cellular level, together with the other signalling pathways, to produce the functional limb capable of co- ordinated precise movements. KEY WORDS: Wnt, limb, development, chondrogenesis, myogenesis The Wnt Gene Family is found in the others (Cadigan and Nusse, 1997). The frizzled receptors can function together with the LRP co-receptors, which The Wnt family of secreted glycosylated factors consists of 22 are single transmembrane proteins containing LDL receptor re- members in vertebrates which have a range of functions during peats, two frizzled motifs and four EGF type repeats in the development from patterning individual structures to fine tuning at extracellular domain (reviewed by Pandur and Kühl, 2001; also see a cellular level controlling cell differentiation, proliferation and Roszmusz et al., 2001). The LRPs, which include the vertebrate survival. The founding members of this family are the Drosophila genes LRP4, -5 and -6 and the Drosophila gene arrow, form a segment polarity gene Wingless (Wg), required for wing develop- complex with frizzled in a Wnt-dependent manner and signal in the ment, together with Wnt1 (originally named int-1) in the mouse. -
Sonic Hedgehog Signaling in Limb Development
REVIEW published: 28 February 2017 doi: 10.3389/fcell.2017.00014 Sonic Hedgehog Signaling in Limb Development Cheryll Tickle 1* and Matthew Towers 2* 1 Department of Biology and Biochemistry, University of Bath, Bath, UK, 2 Department of Biomedical Science, The Bateson Centre, University of Sheffield, Western Bank, Sheffield, UK The gene encoding the secreted protein Sonic hedgehog (Shh) is expressed in the polarizing region (or zone of polarizing activity), a small group of mesenchyme cells at the posterior margin of the vertebrate limb bud. Detailed analyses have revealed that Shh has the properties of the long sought after polarizing region morphogen that specifies positional values across the antero-posterior axis (e.g., thumb to little finger axis) of the limb. Shh has also been shown to control the width of the limb bud by stimulating mesenchyme cell proliferation and by regulating the antero-posterior length of the apical ectodermal ridge, the signaling region required for limb bud outgrowth and the laying down of structures along the proximo-distal axis (e.g., shoulder to digits axis) of the limb. It has been shown that Shh signaling can specify antero-posterior positional values in Edited by: limb buds in both a concentration- (paracrine) and time-dependent (autocrine) fashion. Andrea Erika Münsterberg, University of East Anglia, UK Currently there are several models for how Shh specifies positional values over time in the Reviewed by: limb buds of chick and mouse embryos and how this is integrated with growth. Extensive Megan Davey, work has elucidated downstream transcriptional targets of Shh signaling. Nevertheless, it University of Edinburgh, UK Robert Hill, remains unclear how antero-posterior positional values are encoded and then interpreted University of Edinburgh, UK to give the particular structure appropriate to that position, for example, the type of digit. -
Of Limb Morphogenesis in a Model System
DEVELOPMENTAL BIOLOGY 28, 113-122 (1972) Analysis of Limb Morphogenesis in a Model System ROBERT H. SINGER’. 2 Department of Biology, Brandeis University, Waltham, Massachusetts Accepted January 27, 1972 A method for analysis of chicken limb morphogenesis was devised. This method consisted of grafting a limb ectodermal jacket containing dissociated and pelleted mesenchymal cellular com- ponents to the host somites. Different cellular components stuffed into the ectoderm could be mixed in varied ratios. After 7 days the grafts were analyzed for outgrowth. Stage 19 mesoblast cells alone when treated as above gave limblike outgrowths with good digits, toes, and claws in all cases. However, mesoblasts from the proximal half of older limbs (stages 24, 25 and chondro- cytes) gave no outgrowths, and those from stage 23 gave outgrowths in 9% of the cases. In mixtures of 5% stage 19 cells with 95% chondrocytes, consistent morphogenesis (i.e., in 65% of grafts) oc- curred. The amount of morphogenesis (size of graft and perfection of digits) was directly propor- tional to the amount of stage 19 cells. However, these cells mixed with proximal cells of stages 23, 24, or 25 required higher proportions for equivalent morphogenesis. To obtain morphogenesis equivalent to the 5% mixture with chondrocytes, 10% stage 19 cells were needed when mixed with proximal stage 23, 25% with proximal stage 24 and 7% with proximal stage 25. Mixtures of stage 19 cells added to nonlimb (flank, stage- 19) mesoderm, formed large tumorous mounds of tissue with no limblike features. INTRODUCTION ectoderm ridge serves as a specific induc- The limb bud presents a good model of tive structure initiating and directing out- a developing system. -
Upper Limb Development
Upper Limb Development Alphonsus Chong Department of Hand and Reconstructive Microsurgery National University Hospital Why bother? Most congenital limb anomalies are due to: Disorders of embryogenesis or Problems during fetal development Some terminology Embryogenesis 0-8 weeks – new organ systems appear Fetal period Appearance of primary ossification center in humerus Differentiation, maturation and enlargement of existing organs Limb Development Limb Patterning Tissue Differentiation Why is it an arm and not Skeletal a leg? Joint Vascular Nerve Muscle and Tendon Positional Information and Axes of the upper limb Limb Bud in E3 Chick Embryo Limb bud (lateral plate) Loose mesenchymal cells from lateral plate mesoderm Ectodermal epithelial cells Migrating cells Somites --> Muscle Nerves Vasculature Limb Bud Development Limb bud Ectoderm and mesenchyme Not fully differentiated yet but all ingredients there If transplanted ectopic limb Limb Bud Regions AER Progress zone Zone of polarizing activity AER – Proximal to Distal formation Zone of Polarizing Actvity – AP development Morphogen Gradient Model Dorsal / ventral patterning less well understood Separation of Digits Apoptosis (Programmed cell death) of interdigital mesenchyme BMPs important Starts post-axial to pre-axial Mesoderm specifies amount of apoptosis How does this relate to pathogensis? Picture from Greene Learning Points UE development occurs early in embryogenesis – most risk of development congenital anomalies Pattern of limb development follows a body plan Digit formation is by apoptosis Thank You Further Reading Principles of Development 3rd Ed by Lewis Wolpert. Oxford University Press Growing Hand. Amit Gupta and Louisville Group. -
The Roles of Fgfs in the Early Development of Vertebrate Limbs
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The roles of FGFs in the early development of vertebrate limbs Gail R. Martin1 Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California at San Francisco, San Francisco, California 94143–0452 USA ‘‘Fibroblast growth factor’’ (FGF) was first identified 25 tion of two closely related proteins—acidic FGF and ba- years ago as a mitogenic activity in pituitary extracts sic FGF (now designated FGF1 and FGF2, respectively). (Armelin 1973; Gospodarowicz 1974). This modest ob- With the advent of gene isolation techniques it became servation subsequently led to the identification of a large apparent that the Fgf1 and Fgf2 genes are members of a family of proteins that affect cell proliferation, differen- large family, now known to be comprised of at least 17 tiation, survival, and motility (for review, see Basilico genes, Fgf1–Fgf17, in mammals (see Coulier et al. 1997; and Moscatelli 1992; Baird 1994). Recently, evidence has McWhirter et al. 1997; Hoshikawa et al. 1998; Miyake been accumulating that specific members of the FGF 1998). At least five of these genes are expressed in the family function as key intercellular signaling molecules developing limb (see Table 1). The proteins encoded by in embryogenesis (for review, see Goldfarb 1996). Indeed, the 17 different FGF genes range from 155 to 268 amino it may be no exaggeration to say that, in conjunction acid residues in length, and each contains a conserved with the members of a small number of other signaling ‘‘core’’ sequence of ∼120 amino acids that confers a com- molecule families [including WNT (Parr and McMahon mon tertiary structure and the ability to bind heparin or 1994), Hedgehog (HH) (Hammerschmidt et al. -
Homeobox Genes D11–D13 and A13 Control Mouse Autopod Cortical
Research article Homeobox genes d11–d13 and a13 control mouse autopod cortical bone and joint formation Pablo Villavicencio-Lorini,1,2 Pia Kuss,1,2 Julia Friedrich,1,2 Julia Haupt,1,2 Muhammed Farooq,3 Seval Türkmen,2 Denis Duboule,4 Jochen Hecht,1,5 and Stefan Mundlos1,2,5 1Max Planck Institute for Molecular Genetics, Berlin, Germany. 2Institute for Medical Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany. 3Human Molecular Genetics Laboratory, National Institute for Biotechnology & Genetic Engineering (NIBGE), Faisalabad, Pakistan. 4National Research Centre Frontiers in Genetics, Department of Zoology and Animal Biology, University of Geneva, Geneva, Switzerland. 5Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité, Universitätsmedizin Berlin, Berlin, Germany. The molecular mechanisms that govern bone and joint formation are complex, involving an integrated network of signaling pathways and gene regulators. We investigated the role of Hox genes, which are known to specify individual segments of the skeleton, in the formation of autopod limb bones (i.e., the hands and feet) using the mouse mutant synpolydactyly homolog (spdh), which encodes a polyalanine expansion in Hoxd13. We found that no cortical bone was formed in the autopod in spdh/spdh mice; instead, these bones underwent trabecular ossification after birth. Spdh/spdh metacarpals acquired an ovoid shape and developed ectopic joints, indicating a loss of long bone characteristics and thus a transformation of metacarpals into carpal bones. The perichon- drium of spdh/spdh mice showed abnormal morphology and decreased expression of Runt-related transcription factor 2 (Runx2), which was identified as a direct Hoxd13 transcriptional target. Hoxd11–/–Hoxd12–/–Hoxd13–/– tri- ple-knockout mice and Hoxd13–/–Hoxa13+/– mice exhibited similar but less severe defects, suggesting that these Hox genes have similar and complementary functions and that the spdh allele acts as a dominant negative. -
Patterning Mechanisms Controlling Vertebrate Limb Development
8 Sep 2001 13:46 AR AR139-4.tex AR139-4.SGM ARv2(2001/05/10) P1: GSR Annu. Rev. Cell Dev. Biol. 2001. 17:87–132 Copyright c 2001 by Annual Reviews. All rights reserved PATTERNING MECHANISMS CONTROLLING VERTEBRATE LIMB DEVELOPMENT Javier Capdevila and Juan Carlos Izpisua´ Belmonte The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037; e-mail: [email protected]; [email protected] Key Words AER, BMP, FGF, Hedgehog, limb, morphogen, pattern formation, regeneration, secreted factors, vertebrate development, WNT, ZPA ■ Abstract Vertebrate limb buds are embryonic structures for which much molecu- lar and cellular data are known regarding the mechanisms that control pattern formation during development. Specialized regions of the developing limb bud, such as the zone of polarizing activity (ZPA), the apical ectodermal ridge (AER), and the non-ridge ectoderm, direct and coordinate the development of the limb bud along the anterior- posterior (AP), dorsal-ventral (DV), and proximal-distal (PD) axes, giving rise to a stereotyped pattern of elements well conserved among tetrapods. In recent years, spe- cific gene functions have been shown to mediate the organizing and patterning activities of the ZPA, the AER, and the non-ridge ectoderm. The analysis of these gene functions has revealed the existence of complex interactions between signaling pathways oper- ated by secreted factors of the HH, TGF-/BMP, WNT, and FGF superfamilies, which interact with many other genetic networks to control limb positioning, outgrowth, and patterning. The study of limb development has helped to establish paradigms for the analysis of pattern formation in many other embryonic structures and organs. -
Wnt/ß-Catenin Signaling Regulates Vertebrate Limb Regeneration
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION  epithelia that, like the regenerating AEC, is required for Wnt/ -catenin signaling the proliferation of mesenchymal cells, and therefore for regulates vertebrate limb normal limb development. Here we show that reduction in Wnt and BMP signaling during limb regeneration in regeneration axolotls, Xenopus laevis, and zebrafish induce alter- ations in the formation of the AEC that prevent normal 1 Yasuhiko Kawakami, Concepción Rodriguez fin/limb regeneration. More importantly, by performing Esteban,1 Marina Raya,2 Hiroko Kawakami,1 gain of function experiments of the Wnt/-catenin path- Merce`Martı´,2 Ilir Dubova,1,2 and way during appendage regeneration, we demonstrate Juan Carlos Izpisúa Belmonte1,2,3 that this pathway promotes Xenopus and zebrafish limb/ fin regeneration. The ability of this pathway to promote 1Gene Expression Laboratory, The Salk Institute for Biological regeneration is not only restricted to normally regener- Studies, La Jolla, California 92037, USA; 2Center for ating organisms, since activation of Wnt signaling during Regenerative Medicine of Barcelona, 08003 Barcelona, Spain limb development in the chick embryo enables regenera- tion of the AER. While obviously not identical processes, The cellular and molecular bases allowing tissue regen- the similarities encountered in the molecular and cellu- eration are not well understood. By performing gain- and lar processes involved during limb embryogenesis and loss-of-function experiments of specific members of the limb regeneration suggest a mechanism whereby varia- Wnt pathway during appendage regeneration, we dem- tions in the concentration and/or spatiotemporal distri- onstrate that this pathway is not only necessary for re- bution of developmental regulators may allow regenera- tion to occur. -
Skeletal Development in Human: a Model for the Study of Developmental Genes Page 1 Sur 10
Skeletal development in human: a model for the study of developmental genes Page 1 sur 10 Atlas of Genetics and Cytogenetics in Oncology and Haematology Home Genes Leukemias Tumors Cancer prone Deep Insight Portal Teaching Skeletal development in human: a model for the study of developmental genes * I- Introduction I-1. Developmental genes in Drosophila I-2. Skeletal development in human II- Development of the axial skeleton II-1. Signaling molecules involved in the determination of sclerotome to cartilage II- 2. Role of Hox genes in the regulation of vertebral segments III- Development of the limbs (appendicular skeleton) III-1. Limb bud differentiation with respect to three axes III-2. Role of FGF and their receptors in limb development III-3. The role of Hox and BMP genes in the limb bud development IV- Development of the skull IV-1. Signalling molecules involved in craniofacial development V- Conclusion * I. Introduction Our understanding of the genetic and molecular control of development in vertebrates has dramatically increased during the last 10 years through the discovery that molecular processes that control development in invertebrates have been conserved during evolution and are also found in vertebrates. Important developmental genes were identified that are not only similar in sequence but also in their molecular function in widely diverged organisms such as C.elegans, Drosophila, zebrafish, mice and man. From Drosophila studies it is now clear that epigenetic development is regulated by cascades of gene expression. Early acting regulatory genes initiate the developmental process and induce the expression of other downstream genes. http://www.infobiogen.fr/services/chromcancer/IntroItems/GenDevelLongEngl.html 25/01/2006 Skeletal development in human: a model for the study of developmental genes Page 2 sur 10 I.1 Developmental genes in Drosophila Phenotypic analysis of Drosophila mutants has allowed identification in the early eighties of more than 50 developmental genes that fall into three broad classes: 1. -
8. Limb Development
8. LIMB DEVELOPMENT Dr. Ann-Judith Silverman Department of Anatomy & Cell Biology Telephone: 212 305-3540 E-mail: [email protected] RECOMMENDED READING: Larsen’s Human Embryology, 3rd Edition, pages 315-328, 335-342 LEARNING OBJECTIVES: You should be able to: 1. Compare the contribution made by lateral plate (somatopleure) mesoderm and somitic (paraxial) mesoderm to the formation of the limb. 2. Follow the consequence of limb rotation on the innervation pattern of adult limbs. 3. Discuss the signaling mechanisms between the zone of polarizing activity and the apical ectodermal ridge in the anterior-posterior patterning of hand. 4. Describe the novel biochemistry whereby sonic hedgehog establishes a concentration gradient in the limb. GLOSSARY: Apical ectodermal ridge (AER) - most distal rim of epithelium of the limb bud. It is a major signalling center in regulating patterning of the limb and apoptosis in underlying mesoderm (see lecture on Apoptosis). Fibroblast growth factor (FGF) - FGF-4, a secreted protein from the AER overlying the ZPA, regu- lates the expression of SHH. Induction: the change in a cell or tissue’s fate due to a signal from another tissue or cell. Morphogen: A secreted molecule that regulates induction. A concentration gradient of the molecule is frequently established. Progress Zone (PZ) - mesoderm below AER where cellular proliferation takes place. Sonic hedgehog (SHH)- a member of the “hedgehog family” of secreted signalling proteins. SHH is made by the ZPA (below) and regulates anterior/poterior patterning. Zone of Polarizing Activity (ZPA) - mesenchyme just below the AER on the posterior boundary of the limb bud. Major signalling center for the regulation of anterior/posterior patterning. -
Injuries and Normal Variants of the Pediatric Knee
Revista Chilena de Radiología, año 2016. ARTÍCULO DE REVISIÓN Injuries and normal variants of the pediatric knee Cristián Padilla C.a,* , Cristián Quezada J.a,b, Nelson Flores N.a, Yorky Melipillán A.b and Tamara Ramírez P.b a. Imaging Center, Hospital Clínico Universidad de Chile, Santiago, Chile. b. Radiology Service, Hospital de Niños Roberto del Río, Santiago, Chile. Abstract: Knee pathology is a reason for consultation and a prevalent condition in children, which is why it is important to know both the normal variants as well as the most frequent pathologies. In this review a brief description is given of the main pathologies and normal variants that affect the knee in children, not only the main clinical characteristics but also the findings described in the different, most used imaging techniques (X-ray, ultrasound, computed tomography and magnetic resonance imaging [MRI]). Keywords: Knee; Paediatrics; Bone lesions. Introduction posteromedial distal femoral metaphysis, near the Pediatric knee imaging studies are used to evaluate insertion site of the medial twin muscle or adductor different conditions, whether traumatic, inflammatory, magnus1. It is a common finding on radiography and developmental or neoplastic. magnetic resonance imaging (MRI), incidental, with At a younger age the normal evolution of the more frequency between ages 10-15 years, although images during the skeletal development of the distal it can be present at any age until the physeal closure, femur, proximal tibia and proximal fibula should be after which it resolves1. In frontal radiography, it ap- known to avoid diagnostic errors. Older children and pears as a radiolucent, well circumscribed, cortical- adolescents present a higher frequency of traumatic based lesion with no associated soft tissue mass, with and athletic injuries. -
Determining the Role of Wnt5a Signaling in Embryonic Limb Outgrowth Via Clonal Analysis
Brigham Young University BYU ScholarsArchive Theses and Dissertations 2008-08-14 Determining the Role of Wnt5a Signaling in Embryonic Limb Outgrowth via Clonal Analysis Whitney Herrod Sowby Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Cell and Developmental Biology Commons, and the Physiology Commons BYU ScholarsArchive Citation Sowby, Whitney Herrod, "Determining the Role of Wnt5a Signaling in Embryonic Limb Outgrowth via Clonal Analysis" (2008). Theses and Dissertations. 1638. https://scholarsarchive.byu.edu/etd/1638 This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. DETERMINING THE ROLE OF WNT5A IN EMBRYONIC LIMB OUTGROWTH VIA CLONAL ANALYSIS by Whitney Herrod Sowby A thesis submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Master of Science Department of Physiology and Developmental Biology Brigham Young University December 2008 Copyright © 2008 Whitney Herrod Sowby All Rights Reserved BRIGHAM YOUNG UNIVERSITY GRADUATE COMMITTEE APPROVAL of a thesis submitted by Whitney Herrod Sowby This thesis has been read by each member of the following graduate committee and by majority vote has been found to be satisfactory. Date Jeffery R. Barrow, Chair Date Michael R. Stark Date Laura C. Bridgewater BRIGHAM YOUNG UNIVERSITY As chair of the candidate’s graduate committee, I have read the thesis of Whitney Herrod Sowby in its final form and have found that (1) its format, citations, and bibliographical style are consistent and acceptable and fulfill university and department style requirements; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the graduate committee and is ready for submission to the university library.