DOI: 10.1242/dev.121.12.4329. Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme

Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme

10.1242/dev.121.12.4329

Crossref journal-article

The Company of Biologists

Development (237)

Abstract

ABSTRACT The developing chick limb has two major signalling centres; the apical ectodermal ridge maintains expression of several important genes and outgrowth of the limb, and the polarising region specifies the pattern of skeletal elements along the anteroposterior axis. We have used reaggregated leg grafts (mesenchyme dissociated into single cells, placed in an ectodermal jacket and grafted to a host) to study patterning in a system where the developmental axes are severely disrupted. Reaggregates from different regions of leg mesenchyme developed corre-spondingly different digits, giving a system in which skeletal phenotype could be compared with the expression of genes thought to be important in patterning. We found that posterior third and whole leg reaggregates gave rise to different digits, yet expressed the same combination of HoxD, Bmp-2 and shh genes throughout their development. Anterior thirds initially only express the 3′ end of the HoxD cluster but activate the more 5′ members of the cluster sequentially over a period of 48 hours, a period during which Bmp-2 is activated but no shh or Fgf-4 expression could be detected. Our results suggest that there are two independent mechanisms for activating the HoxD complex, one polarising region-dependent and one independent, and that shh expression may not be necessary to maintain outgrowth and patterning once a ridge has been established.

Bibliography

Hardy, A., Richardson, M. K., Francis-West, P. H., Rodriguez, C., IzpisÃºa-Belmonte, J.-C., Duprez, D., & Wolpert, L. (1995). Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme. Development, 121(12), 4329â4337.

Authors 7

Adrian Hardy (first)
Michael K. Richardson (additional)
Philippa H. Francis-West (additional)
Concepción Rodriguez (additional)
Juan-Carlos Izpisúa-Belmonte (additional)
Delphine Duprez (additional)
Lewis Wolpert (additional)

References 51 Referenced 38

10.1038/368208a0 / Nature / Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein by Basler (1994)
10.1242/dev.121.7.1971 / Development / Polydactylous limbs in Strong’s Luxoid mice result from ectopic polarizing activity by Chan (1995)
10.1016/0092-8674(95)90352-6 / Cell / Fibroblast growth factors induce additional limb development from the flank of chick embryos by Cohn (1995)
10.1016/0012-1606(75)90084-6 / Dev. Biol / Inhibitory effect on limb morphogenesis by cells of the polarising zone coaggregated with pre- or postaxial wing bud mesoderm by Crosby (1975)
10.1242/dev.121.2.439 / Development / The mouse Fgf-8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo by Crossley (1995)
10.1242/dev.104.2.305 / Development / A gene with sequence similarity to Drosophila engrailed is expressed during the development of the neural tube and vertebrae in the mouse by Davidson (1988)
10.1242/dev.120.8.2187 / Development / Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of Hoxd-11 by Davis (1994)
10.1038/375791a0 / Nature / Absence of radius and ulna in mice lacking Hoxa-11 and Hoxd-11 by Davis (1995)
10.1038/372175a0 / Nature / Cell interaction between compartments establishes the proximal-distal axis of Drosophila legs by Diaz-Benjumea (1994)
10.1038/342767a0 / Nature / Coordinate expression of the murine Hox-5 complex homeobox-containing genes during limb pattern formation by Dollé (1989)
10.1016/0092-8674(93)90378-4 / Cell / Disruption of the Hoxd-13 gene induces localised heterochrony leading to mice with neotenic limbs by Dollé (1993)
10.1242/dev.1994.Supplement.135 / Development Supplement, 135-142 / Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony by Duboule (1994)
{'key': '2025011515280317600_DEVELOP_121_12_4329C13', 'first-page': '43', 'article-title': 'The hedgehog gene family in Drosophila and vertebrate development', 'volume-title': 'Development', 'author': 'Feitz', 'year': '1994'} / Development / The hedgehog gene family in Drosophila and vertebrate development by Feitz (1994)
10.1242/dev.120.1.209 / Development / Bone morphogenetic proteins and a signalling pathway that controls patterning in the developing chick limb by Francis (1994)
10.1002/aja.1002030207 / Dev. Dynam / Expression of genes encoding Bone morphogenetic proteins and Sonic hedgehog in talpid (ta3) limb buds: Their relationships in the signalling cascade involved in limb patterning by Francis-West (1995)
{'key': '2025011515280317600_DEVELOP_121_12_4329C16', 'first-page': '13', 'article-title': 'The proportion and distribution of polarising zone cells causing morphogenetic inhibition when coaggregated with anterior half wing mesoderm in recombinant limbs', 'volume': '67', 'author': 'Frederick', 'year': '1982', 'journal-title': 'J. Embryol. exp. Morphol'} / J. Embryol. exp. Morphol / The proportion and distribution of polarising zone cells causing morphogenetic inhibition when coaggregated with anterior half wing mesoderm in recombinant limbs by Frederick (1982)
10.1002/jmor.1050880104 / J. Morphol / A series of normal stages in the development of the chick embryo by Hamburger (1951)
10.1006/dbio.1995.1150 / Dev. Biol / Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: Evidence for unique and redundant function by Horan (1995)
10.1146/annurev.cb.08.110192.001303 / Annu. Rev. Cell Biol / Hox codes and positional specification in vertebrate embryonic axes by Hunt (1992)
10.1038/350585a0 / Nature / Expression of the homeobox Hox-4 genes and the specification of position in chick wing development by Izpisúa-Belmonte (1991)
10.1242/dev.115.2.553 / Development / Hox-4 gene expression in mouse/chicken heterospecific grafts of signalling regions to limb buds reveals similarities in patterning mechanisms by Izpisúa-Belmonte (1992)
10.1002/j.1460-2075.1992.tb05189.x / EMBO J / Expression of Hox-4 genes in the chick wing links pattern formation to the epithelial-mesenchymal interactions that mediate growth by Izpisúa-Belmonte (1992)
10.1016/0092-8674(93)90512-O / Cell / The Homeobox gene goosecoid and the origin of organiser cells in the early chick blastoderm by Izpisúa-Belmonte (1993)
10.1016/0092-8674(94)90030-2 / Cell / Sonic hedgehog and Fgf-4 act through a signalling cascade and feedback loop to integrate growth and patterning of the developing limb bud by Laufer (1994)
10.1016/S0960-9822(95)00156-4 / Curr. Biol / Limb-patterning activity and restricted posterior localization of the amino-terminal product of Sonic hedgehog cleavage by López-Martínez (1995)
10.1016/0012-1606(73)90269-8 / Dev. Biol / The control of the anteroposterior and dorsoventral axes in embryonic chick limbs constructed of dissociated and reaggregated limb-bud mesoderm by MacCabe (1973)
10.1242/dev.112.3.791 / Development / GHox-4.7: A chick homeobox gene expressed primarily in limb buds with limb-type differences in expression by Mackem (1991)
10.1016/S0960-9822(95)00157-6 / Curr. Biol / A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth by Mahmood (1995)
10.1101/gad.9.13.1645 / Genes Dev / A duplicated zone of polarizing activity in polydactylous mouse mutants by Masuya (1995)
10.1038/358236a0 / Nature / Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformation by Morgan (1992)
{'key': '2025011515280317600_DEVELOP_121_12_4329C31', 'first-page': '181', 'article-title': 'Hox genes and growth: Early and late roles in limb bud morphogenesis', 'volume-title': 'Development', 'author': 'Morgan', 'year': '1994'} / Development / Hox genes and growth: Early and late roles in limb bud morphogenesis by Morgan (1994)
10.1242/dev.114.3.755 / Development / Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse by Niswander (1992)
10.1016/0092-8674(93)90391-3 / Cell / FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb by Niswander (1993)
10.1038/371609a0 / Nature / A positive feedback loop coordinates growth and patterning in the vertebrate limb by Niswander (1994)
10.1016/0092-8674(93)90626-2 / Cell / Sonic hedgehog mediates the polarising activity of the ZPA by Riddle (1993)
10.1242/dev.118.1.95 / Development / Retroviral expression of FGF-2 (bFGF) affects patterning in chick limb bud by Riley (1993)
10.1006/dbio.1994.1296 / Dev. Biol / Recombinant limbs as a model to study homeobox gene regulation during limb development by Ros (1994)
10.1242/dev.65.Supplement.309 / J. Embryol. exp. Morphol. 65 (Supplement), 309-325 / The effect of removing posterior apical ectodermal ridge of the chick wing and leg on pattern formation by Rowe (1981)
10.1242/dev.111.4.1007 / Development / Retinoic acid treatment alters the distribution of retinoic acid receptor-β transcripts in the embryonic chick face by Rowe (1991)
10.1002/jez.1401080304 / J. Exp. Zool / The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm by Saunders (1948)
{'key': '2025011515280317600_DEVELOP_121_12_4329C41', 'first-page': '78', 'article-title': 'Ectodermal-mesenchymal interactions in the origin of limb symmetry', 'volume-title': 'Epithelial and Mesenchymal Interactions', 'author': 'Saunders', 'year': '1968'} / Epithelial and Mesenchymal Interactions / Ectodermal-mesenchymal interactions in the origin of limb symmetry by Saunders (1968)
10.1002/aja.1001980302 / Dev. Dynam / Distribution of FGF-2 suggests it has a role in chick limb bud growth by Savage (1993)
10.1016/0092-8674(92)90588-4 / Cell / Vertebrate homeobox nomenclature by Scott (1992)
10.1016/0012-1606(72)90130-3 / Dev. Biol / Analysis of limb morphogenesis in a model system by Singer (1972)
{'key': '2025011515280317600_DEVELOP_121_12_4329C45', 'first-page': '105', 'article-title': 'Evidence for a positional memory in the development of the chick wing bud', 'volume': '52', 'author': 'Smith', 'year': '1979', 'journal-title': 'J. Embryol. exp. Morph'} / J. Embryol. exp. Morph / Evidence for a positional memory in the development of the chick wing bud by Smith (1979)
{'key': '2025011515280317600_DEVELOP_121_12_4329C46', 'first-page': '651', 'article-title': 'A quantitative analysis of the effect of excision of the AER from the chick limb-bud', 'volume': '32', 'author': 'Summerbell', 'year': '1974', 'journal-title': 'J. Embryol. exp. Morphol'} / J. Embryol. exp. Morphol / A quantitative analysis of the effect of excision of the AER from the chick limb-bud by Summerbell (1974)
10.1016/0092-8674(91)90612-3 / Cell / Retinoids, homeoboxes, and growth factors: Toward molecular models for limb development by Tabin (1991)
10.1146/annurev.cb.10.110194.001005 / Annu. Rev. Cell Biol / Vertebrate limb development by Tickle (1994)
10.1242/dev.119.1.199 / Development / FGF-4 maintains polarising activity of posterior limb bud cells in vivo and in vitro by Vogel (1993)
10.1038/353443a0 / Nature / Homeobox gene expression correlated with the bifurcation process of limb cartilage development by Yokouchi (1991)
10.1016/0012-1606(64)90012-0 / Dev. Biol / Development of fragmented and of dissociated limb bud mesoderm by Zwilling (1964)

Dates

Type	When
Created	4 years, 4 months ago (April 25, 2021, 10:16 p.m.)
Deposited	7 months, 1 week ago (Jan. 15, 2025, 10:28 a.m.)
Indexed	7 months, 1 week ago (Jan. 15, 2025, 11:10 a.m.)
Issued	29 years, 8 months ago (Dec. 1, 1995)
Published	29 years, 8 months ago (Dec. 1, 1995)
Published Online	29 years, 8 months ago (Dec. 1, 1995)
Published Print	29 years, 8 months ago (Dec. 1, 1995)

Funders 0

None

BibTeX

@article{Hardy_1995, title={Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme}, volume={121}, ISSN={1477-9129}, url={http://dx.doi.org/10.1242/dev.121.12.4329}, DOI={10.1242/dev.121.12.4329}, number={12}, journal={Development}, publisher={The Company of Biologists}, author={Hardy, Adrian and Richardson, Michael K. and Francis-West, Philippa H. and Rodriguez, Concepción and Izpisúa-Belmonte, Juan-Carlos and Duprez, Delphine and Wolpert, Lewis}, year={1995}, month=dec, pages={4329–4337} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        1,
        15
      ]
    ],
    "date-time": "2025-01-15T16:10:08Z",
    "timestamp": 1736957408882,
    "version": "3.33.0"
  },
  "reference-count": 51,
  "publisher": "The Company of Biologists",
  "issue": "12",
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        1995,
        12,
        1
      ]
    ]
  },
  "abstract": "<jats:title>ABSTRACT</jats:title>\n               <jats:p>The developing chick limb has two major signalling centres; the apical ectodermal ridge maintains expression of several important genes and outgrowth of the limb, and the polarising region specifies the pattern of skeletal elements along the anteroposterior axis. We have used reaggregated leg grafts (mesenchyme dissociated into single cells, placed in an ectodermal jacket and grafted to a host) to study patterning in a system where the developmental axes are severely disrupted. Reaggregates from different regions of leg mesenchyme developed corre-spondingly different digits, giving a system in which skeletal phenotype could be compared with the expression of genes thought to be important in patterning.</jats:p>\n               <jats:p>We found that posterior third and whole leg reaggregates gave rise to different digits, yet expressed the same combination of HoxD, Bmp-2 and shh genes throughout their development. Anterior thirds initially only express the 3\u2032 end of the HoxD cluster but activate the more 5\u2032 members of the cluster sequentially over a period of 48 hours, a period during which Bmp-2 is activated but no shh or Fgf-4 expression could be detected. Our results suggest that there are two independent mechanisms for activating the HoxD complex, one polarising region-dependent and one independent, and that shh expression may not be necessary to maintain outgrowth and patterning once a ridge has been established.</jats:p>",
  "DOI": "10.1242/dev.121.12.4329",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2021,
        4,
        26
      ]
    ],
    "date-time": "2021-04-26T02:16:51Z",
    "timestamp": 1619403411000
  },
  "page": "4329-4337",
  "source": "Crossref",
  "is-referenced-by-count": 38,
  "title": "Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme",
  "prefix": "10.1242",
  "volume": "121",
  "author": [
    {
      "given": "Adrian",
      "family": "Hardy",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Department of Anatomy and Developmental Biology 1 , University College London, Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Michael K.",
      "family": "Richardson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Anatomy and Developmental Biology 1 , University College London, Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Philippa H.",
      "family": "Francis-West",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Anatomy and Developmental Biology 1 , University College London, Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        },
        {
          "name": "Department of Molecular Pathology 2 , University College London, Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Concepci\u00f3n",
      "family": "Rodriguez",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Gene Expression Laboratories 3 , The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA"
        }
      ]
    },
    {
      "given": "Juan-Carlos",
      "family": "Izpis\u00faa-Belmonte",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Gene Expression Laboratories 3 , The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA"
        }
      ]
    },
    {
      "given": "Delphine",
      "family": "Duprez",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Molecular Pathology 2 , University College London, Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Lewis",
      "family": "Wolpert",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Anatomy and Developmental Biology 1 , University College London, Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    }
  ],
  "member": "237",
  "published-online": {
    "date-parts": [
      [
        1995,
        12,
        1
      ]
    ]
  },
  "reference": [
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C1",
      "doi-asserted-by": "publisher",
      "first-page": "208",
      "DOI": "10.1038/368208a0",
      "article-title": "Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein",
      "volume": "368",
      "author": "Basler",
      "year": "1994",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C2",
      "doi-asserted-by": "publisher",
      "first-page": "1971",
      "DOI": "10.1242/dev.121.7.1971",
      "article-title": "Polydactylous limbs in Strong\u2019s Luxoid mice result from ectopic polarizing activity",
      "volume": "121",
      "author": "Chan",
      "year": "1995",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C3",
      "doi-asserted-by": "publisher",
      "first-page": "739",
      "DOI": "10.1016/0092-8674(95)90352-6",
      "article-title": "Fibroblast growth factors induce additional limb development from the flank of chick embryos",
      "volume": "80",
      "author": "Cohn",
      "year": "1995",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C4",
      "doi-asserted-by": "publisher",
      "first-page": "28",
      "DOI": "10.1016/0012-1606(75)90084-6",
      "article-title": "Inhibitory effect on limb morphogenesis by cells of the polarising zone coaggregated with pre- or postaxial wing bud mesoderm",
      "volume": "46",
      "author": "Crosby",
      "year": "1975",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C5",
      "doi-asserted-by": "publisher",
      "first-page": "439",
      "DOI": "10.1242/dev.121.2.439",
      "article-title": "The mouse Fgf-8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo",
      "volume": "121",
      "author": "Crossley",
      "year": "1995",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C6",
      "doi-asserted-by": "publisher",
      "first-page": "305",
      "DOI": "10.1242/dev.104.2.305",
      "article-title": "A gene with sequence similarity to Drosophila engrailed is expressed during the development of the neural tube and vertebrae in the mouse",
      "volume": "104",
      "author": "Davidson",
      "year": "1988",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C7",
      "doi-asserted-by": "publisher",
      "first-page": "2187",
      "DOI": "10.1242/dev.120.8.2187",
      "article-title": "Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of Hoxd-11",
      "volume": "120",
      "author": "Davis",
      "year": "1994",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C8",
      "doi-asserted-by": "publisher",
      "first-page": "791",
      "DOI": "10.1038/375791a0",
      "article-title": "Absence of radius and ulna in mice lacking Hoxa-11 and Hoxd-11",
      "volume": "375",
      "author": "Davis",
      "year": "1995",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C9",
      "doi-asserted-by": "publisher",
      "first-page": "175",
      "DOI": "10.1038/372175a0",
      "article-title": "Cell interaction between compartments establishes the proximal-distal axis of Drosophila legs",
      "volume": "372",
      "author": "Diaz-Benjumea",
      "year": "1994",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C10",
      "doi-asserted-by": "publisher",
      "first-page": "767",
      "DOI": "10.1038/342767a0",
      "article-title": "Coordinate expression of the murine Hox-5 complex homeobox-containing genes during limb pattern formation",
      "volume": "342",
      "author": "Doll\u00e9",
      "year": "1989",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C11",
      "doi-asserted-by": "publisher",
      "first-page": "431",
      "DOI": "10.1016/0092-8674(93)90378-4",
      "article-title": "Disruption of the Hoxd-13 gene induces localised heterochrony leading to mice with neotenic limbs",
      "volume": "75",
      "author": "Doll\u00e9",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C12",
      "doi-asserted-by": "crossref",
      "DOI": "10.1242/dev.1994.Supplement.135",
      "article-title": "Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony",
      "volume-title": "Development Supplement, 135-142",
      "author": "Duboule",
      "year": "1994"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C13",
      "first-page": "43",
      "article-title": "The hedgehog gene family in Drosophila and vertebrate development",
      "volume-title": "Development",
      "author": "Feitz",
      "year": "1994"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C14",
      "doi-asserted-by": "publisher",
      "first-page": "209",
      "DOI": "10.1242/dev.120.1.209",
      "article-title": "Bone morphogenetic proteins and a signalling pathway that controls patterning in the developing chick limb",
      "volume": "120",
      "author": "Francis",
      "year": "1994",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C15",
      "doi-asserted-by": "publisher",
      "first-page": "187",
      "DOI": "10.1002/aja.1002030207",
      "article-title": "Expression of genes encoding Bone morphogenetic proteins and Sonic hedgehog in talpid (ta3) limb buds: Their relationships in the signalling cascade involved in limb patterning",
      "volume": "203",
      "author": "Francis-West",
      "year": "1995",
      "journal-title": "Dev. Dynam"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C16",
      "first-page": "13",
      "article-title": "The proportion and distribution of polarising zone cells causing morphogenetic inhibition when coaggregated with anterior half wing mesoderm in recombinant limbs",
      "volume": "67",
      "author": "Frederick",
      "year": "1982",
      "journal-title": "J. Embryol. exp. Morphol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C17",
      "doi-asserted-by": "publisher",
      "first-page": "49",
      "DOI": "10.1002/jmor.1050880104",
      "article-title": "A series of normal stages in the development of the chick embryo",
      "volume": "88",
      "author": "Hamburger",
      "year": "1951",
      "journal-title": "J. Morphol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C18",
      "doi-asserted-by": "publisher",
      "first-page": "359",
      "DOI": "10.1006/dbio.1995.1150",
      "article-title": "Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: Evidence for unique and redundant function",
      "volume": "169",
      "author": "Horan",
      "year": "1995",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C19",
      "doi-asserted-by": "publisher",
      "first-page": "227",
      "DOI": "10.1146/annurev.cb.08.110192.001303",
      "article-title": "Hox codes and positional specification in vertebrate embryonic axes",
      "volume": "8",
      "author": "Hunt",
      "year": "1992",
      "journal-title": "Annu. Rev. Cell Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C20",
      "doi-asserted-by": "publisher",
      "first-page": "585",
      "DOI": "10.1038/350585a0",
      "article-title": "Expression of the homeobox Hox-4 genes and the specification of position in chick wing development",
      "volume": "350",
      "author": "Izpis\u00faa-Belmonte",
      "year": "1991",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C21",
      "doi-asserted-by": "publisher",
      "first-page": "553",
      "DOI": "10.1242/dev.115.2.553",
      "article-title": "Hox-4 gene expression in mouse/chicken heterospecific grafts of signalling regions to limb buds reveals similarities in patterning mechanisms",
      "volume": "115",
      "author": "Izpis\u00faa-Belmonte",
      "year": "1992",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C22",
      "doi-asserted-by": "publisher",
      "first-page": "1451",
      "DOI": "10.1002/j.1460-2075.1992.tb05189.x",
      "article-title": "Expression of Hox-4 genes in the chick wing links pattern formation to the epithelial-mesenchymal interactions that mediate growth",
      "volume": "11",
      "author": "Izpis\u00faa-Belmonte",
      "year": "1992",
      "journal-title": "EMBO J"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C23",
      "doi-asserted-by": "publisher",
      "first-page": "645",
      "DOI": "10.1016/0092-8674(93)90512-O",
      "article-title": "The Homeobox gene goosecoid and the origin of organiser cells in the early chick blastoderm",
      "volume": "74",
      "author": "Izpis\u00faa-Belmonte",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C24",
      "doi-asserted-by": "publisher",
      "first-page": "993",
      "DOI": "10.1016/0092-8674(94)90030-2",
      "article-title": "Sonic hedgehog and Fgf-4 act through a signalling cascade and feedback loop to integrate growth and patterning of the developing limb bud",
      "volume": "79",
      "author": "Laufer",
      "year": "1994",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C25",
      "doi-asserted-by": "publisher",
      "first-page": "791",
      "DOI": "10.1016/S0960-9822(95)00156-4",
      "article-title": "Limb-patterning activity and restricted posterior localization of the amino-terminal product of Sonic hedgehog cleavage",
      "volume": "5",
      "author": "L\u00f3pez-Mart\u00ednez",
      "year": "1995",
      "journal-title": "Curr. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C26",
      "doi-asserted-by": "publisher",
      "first-page": "323",
      "DOI": "10.1016/0012-1606(73)90269-8",
      "article-title": "The control of the anteroposterior and dorsoventral axes in embryonic chick limbs constructed of dissociated and reaggregated limb-bud mesoderm",
      "volume": "31",
      "author": "MacCabe",
      "year": "1973",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C27",
      "doi-asserted-by": "publisher",
      "first-page": "791",
      "DOI": "10.1242/dev.112.3.791",
      "article-title": "GHox-4.7: A chick homeobox gene expressed primarily in limb buds with limb-type differences in expression",
      "volume": "112",
      "author": "Mackem",
      "year": "1991",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C28",
      "doi-asserted-by": "publisher",
      "first-page": "797",
      "DOI": "10.1016/S0960-9822(95)00157-6",
      "article-title": "A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth",
      "volume": "5",
      "author": "Mahmood",
      "year": "1995",
      "journal-title": "Curr. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C29",
      "doi-asserted-by": "publisher",
      "first-page": "1645",
      "DOI": "10.1101/gad.9.13.1645",
      "article-title": "A duplicated zone of polarizing activity in polydactylous mouse mutants",
      "volume": "9",
      "author": "Masuya",
      "year": "1995",
      "journal-title": "Genes Dev"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C30",
      "doi-asserted-by": "publisher",
      "first-page": "236",
      "DOI": "10.1038/358236a0",
      "article-title": "Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformation",
      "volume": "358",
      "author": "Morgan",
      "year": "1992",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C31",
      "first-page": "181",
      "article-title": "Hox genes and growth: Early and late roles in limb bud morphogenesis",
      "volume-title": "Development",
      "author": "Morgan",
      "year": "1994"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C32",
      "doi-asserted-by": "publisher",
      "first-page": "755",
      "DOI": "10.1242/dev.114.3.755",
      "article-title": "Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse",
      "volume": "114",
      "author": "Niswander",
      "year": "1992",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C33",
      "doi-asserted-by": "publisher",
      "first-page": "579",
      "DOI": "10.1016/0092-8674(93)90391-3",
      "article-title": "FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb",
      "volume": "75",
      "author": "Niswander",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C34",
      "doi-asserted-by": "publisher",
      "first-page": "609",
      "DOI": "10.1038/371609a0",
      "article-title": "A positive feedback loop coordinates growth and patterning in the vertebrate limb",
      "volume": "371",
      "author": "Niswander",
      "year": "1994",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C35",
      "doi-asserted-by": "publisher",
      "first-page": "1401",
      "DOI": "10.1016/0092-8674(93)90626-2",
      "article-title": "Sonic hedgehog mediates the polarising activity of the ZPA",
      "volume": "75",
      "author": "Riddle",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C36",
      "doi-asserted-by": "publisher",
      "first-page": "95",
      "DOI": "10.1242/dev.118.1.95",
      "article-title": "Retroviral expression of FGF-2 (bFGF) affects patterning in chick limb bud",
      "volume": "118",
      "author": "Riley",
      "year": "1993",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C37",
      "doi-asserted-by": "publisher",
      "first-page": "59",
      "DOI": "10.1006/dbio.1994.1296",
      "article-title": "Recombinant limbs as a model to study homeobox gene regulation during limb development",
      "volume": "166",
      "author": "Ros",
      "year": "1994",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C38",
      "doi-asserted-by": "crossref",
      "DOI": "10.1242/dev.65.Supplement.309",
      "article-title": "The effect of removing posterior apical ectodermal ridge of the chick wing and leg on pattern formation",
      "volume-title": "J. Embryol. exp. Morphol. 65 (Supplement), 309-325",
      "author": "Rowe",
      "year": "1981"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C39",
      "doi-asserted-by": "publisher",
      "first-page": "1007",
      "DOI": "10.1242/dev.111.4.1007",
      "article-title": "Retinoic acid treatment alters the distribution of retinoic acid receptor-\u03b2 transcripts in the embryonic chick face",
      "volume": "111",
      "author": "Rowe",
      "year": "1991",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C40",
      "doi-asserted-by": "publisher",
      "first-page": "363",
      "DOI": "10.1002/jez.1401080304",
      "article-title": "The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm",
      "volume": "108",
      "author": "Saunders",
      "year": "1948",
      "journal-title": "J. Exp. Zool"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C41",
      "first-page": "78",
      "article-title": "Ectodermal-mesenchymal interactions in the origin of limb symmetry",
      "volume-title": "Epithelial and Mesenchymal Interactions",
      "author": "Saunders",
      "year": "1968"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C42",
      "doi-asserted-by": "publisher",
      "first-page": "159",
      "DOI": "10.1002/aja.1001980302",
      "article-title": "Distribution of FGF-2 suggests it has a role in chick limb bud growth",
      "volume": "198",
      "author": "Savage",
      "year": "1993",
      "journal-title": "Dev. Dynam"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C43",
      "doi-asserted-by": "publisher",
      "first-page": "551",
      "DOI": "10.1016/0092-8674(92)90588-4",
      "article-title": "Vertebrate homeobox nomenclature",
      "volume": "71",
      "author": "Scott",
      "year": "1992",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C44",
      "doi-asserted-by": "publisher",
      "first-page": "113",
      "DOI": "10.1016/0012-1606(72)90130-3",
      "article-title": "Analysis of limb morphogenesis in a model system",
      "volume": "28",
      "author": "Singer",
      "year": "1972",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C45",
      "first-page": "105",
      "article-title": "Evidence for a positional memory in the development of the chick wing bud",
      "volume": "52",
      "author": "Smith",
      "year": "1979",
      "journal-title": "J. Embryol. exp. Morph"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C46",
      "first-page": "651",
      "article-title": "A quantitative analysis of the effect of excision of the AER from the chick limb-bud",
      "volume": "32",
      "author": "Summerbell",
      "year": "1974",
      "journal-title": "J. Embryol. exp. Morphol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C47",
      "doi-asserted-by": "publisher",
      "first-page": "199",
      "DOI": "10.1016/0092-8674(91)90612-3",
      "article-title": "Retinoids, homeoboxes, and growth factors: Toward molecular models for limb development",
      "volume": "66",
      "author": "Tabin",
      "year": "1991",
      "journal-title": "Cell"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C48",
      "doi-asserted-by": "publisher",
      "first-page": "121",
      "DOI": "10.1146/annurev.cb.10.110194.001005",
      "article-title": "Vertebrate limb development",
      "volume": "10",
      "author": "Tickle",
      "year": "1994",
      "journal-title": "Annu. Rev. Cell Biol"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C49",
      "doi-asserted-by": "publisher",
      "first-page": "199",
      "DOI": "10.1242/dev.119.1.199",
      "article-title": "FGF-4 maintains polarising activity of posterior limb bud cells in vivo and in vitro",
      "volume": "119",
      "author": "Vogel",
      "year": "1993",
      "journal-title": "Development"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C50",
      "doi-asserted-by": "publisher",
      "first-page": "443",
      "DOI": "10.1038/353443a0",
      "article-title": "Homeobox gene expression correlated with the bifurcation process of limb cartilage development",
      "volume": "353",
      "author": "Yokouchi",
      "year": "1991",
      "journal-title": "Nature"
    },
    {
      "key": "2025011515280317600_DEVELOP_121_12_4329C51",
      "doi-asserted-by": "publisher",
      "first-page": "20",
      "DOI": "10.1016/0012-1606(64)90012-0",
      "article-title": "Development of fragmented and of dissociated limb bud mesoderm",
      "volume": "9",
      "author": "Zwilling",
      "year": "1964",
      "journal-title": "Dev. Biol"
    }
  ],
  "container-title": "Development",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://journals.biologists.com/dev/article-pdf/121/12/4329/3120229/develop_121_12_4329.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "https://journals.biologists.com/dev/article-pdf/121/12/4329/3120229/develop_121_12_4329.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2025,
        1,
        15
      ]
    ],
    "date-time": "2025-01-15T15:28:26Z",
    "timestamp": 1736954906000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://journals.biologists.com/dev/article/121/12/4329/38647/Gene-expression-polarising-activity-and-skeletal"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1995,
        12,
        1
      ]
    ]
  },
  "references-count": 51,
  "journal-issue": {
    "issue": "12",
    "published-print": {
      "date-parts": [
        [
          1995,
          12,
          1
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1242/dev.121.12.4329",
  "relation": {},
  "ISSN": [
    "0950-1991",
    "1477-9129"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        1995,
        12,
        1
      ]
    ]
  }
}