DOI: 10.1242/dev.122.6.1821. Activation of <i>Fgf-4</i> and <i>HoxD</i> gene expression by BMP-2 expressing cells in the developing chick limb

Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb

10.1242/dev.122.6.1821

Crossref journal-article

The Company of Biologists

Development (237)

Abstract

ABSTRACT Bone morphogenetic protein-2 (BMP-2) has been implicated in the polarizing region signalling pathway, which specifies pattern across the antero-posterior of the developing vertebrate limb. Retinoic acid and Sonic Hedgehog (SHH) can act as polarizing signals; when applied anteriorly in the limb bud, they induce mirror-image digit duplications and ectopic Bmp-2 expression in anterior mesenchyme. In addition, the two signals can activate Fgf-4 expression in anterior ridge and HoxD expression in anterior mesenchyme. We tested the role of BMP-2 in this signalling cascade by ectopically expressing human BMP-2 (hBMP-2) at the anterior margin of the early wing bud using a replication defective retroviral vector, and found that ectopic expression of Fgf-4 was induced in the anterior part of the apical ectodermal ridge, followed later by ectopic expression of Hoxd-11 and Hoxd-13 in anterior mesenchyme. This suggests that BMP-2 is involved in regulating Fgf-4 and HoxD gene expression in the normal limb bud. Ectopically expressed hBMP-2 also induced duplication of digit 2 and bifurcation of digit 3, but could not produce the mirror-image digit duplications obtained with SHH-expressing cells. These results suggest that BMP-2 may be involved primarily in maintenance of the ridge, and in the link between patterning and outgrowth of the limb bud.

Bibliography

Duprez, D. M., Kostakopoulou, K., Francis-West, P. H., Tickle, C., & Brickell, P. M. (1996). Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb. Development, 122(6), 1821â1828.

Authors 5

Delphine M. Duprez (first)
Konstadina Kostakopoulou (additional)
Philippa H. Francis-West (additional)
Cheryll Tickle (additional)
Paul M. Brickell (additional)

References 45 Referenced 113

10.1016/0012-1606(77)90110-5 / Dev. Biol / Stage related capacity for limb chondrogenesis in cell culture by Ahrens (1977)
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)
10.1242/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.120.8.2187 / Development / Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11 by Davis (1994)
10.1016/0925-4773(93)90035-V / Mech. Dev / Ectopic expression of genes during chicken limb pattern formation using replication defective retroviral vectors by Pompa (1993)
10.1016/0092-8674(93)90378-4 / Cell / Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs by Dollé (1993)
10.1515/9783110861082-009 / In Teratology of the Limbs / Role of the ectoderm in limb development of normal and mutant mouse (Disorganisation, Pupoid Foetus) and fowl (talpid3) embryos by Ede (1980)
10.1242/dev.121.1.1 / Development / Positional signaling by hedgehog in Drosophila imaginal disc development by Felsenfeld (1995)
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)
10.1002/jmor.1050880104 / J. Morphol / A series of normal stages in the development of the chick embryo by Hamburger (1951)
10.1242/dev.121.12.4329 / Development / Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme by Hardy (1995)
10.1016/0092-8674(93)90535-X / Cell / The TGFβ homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina by Heberlein (1993)
10.1128/jvi.61.10.3004-3012.1987 / J. Virol / Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors by Hughes (1987)
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(94)90030-2 / Cell / Sonic hedgehog and Fgf-4 act through a signaling 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)
10.1101/gad.9.22.2808 / Genes Dev / BMP 7 is an inducer of nephrogenesis and is also required for eye development and skeletal patterning by Luo (1995)
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)
10.1016/0092-8674(94)90520-7 / Cell / The ins and outs of fibroblast growth factors by Mason (1994)
10.1101/gad.9.13.1645 / Genes Dev / A duplicated zone of polarizing activity in polydactylous mouse mutants by Masuya (1995)
10.1006/dbio.1995.1053 / Dev. Biol / FGF can induce outgrowth of somatic mesoderm both inside and outside of limb-forming regions by Mima (1995)
10.1038/358236a0 / Nature / Targeted mis-expression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations by Morgan (1992)
{'key': '2025021322573873000_DEVELOP_122_6_1821C27', 'first-page': '181', 'article-title': 'Hox genes and growth: early and late roles in limb bud morphogenesis', 'volume-title': 'Development (supplement)', 'author': 'Morgan', 'year': '1994'} / Development (supplement) / Hox genes and growth: early and late roles in limb bud morphogenesis by Morgan (1994)
10.1038/361068a0 / Nature / FGF-4 and BMP-2 have opposite effects on limb growth by Niswander (1993)
10.1016/0092-8674(93)90391-3 / Cell / FGF-4 replaces the apical actodermal 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)
10.1038/350083a0 / Nature / Retinoic acid induces polarizing activity but is unlikely to be a morphogen in the chick limb bud by Noji (1991)
10.1038/374350a0 / Nature / Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb by Parr (1995)
10.1016/0092-8674(93)90626-2 / Cell / Sonic hedgehog mediates the polarizing 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)
10.1002/aja.1002000203 / Dev. Dynam / Transforming growth factor-β and bone morphogenetic protein-2 act by distinct mechanisms to promote chick limb cartilage differentiation in vitro by Roark (1994)
{'key': '2025021322573873000_DEVELOP_122_6_1821C36', 'first-page': '78', 'article-title': 'Ectodermal-mesenchymal interactions in the origin of limb symmetry', 'volume-title': 'In Epithelial-Mesenchymal Interactions', 'author': 'Saunders', 'year': '1968'} / In Epithelial-Mesenchymal Interactions / Ectodermal-mesenchymal interactions in the origin of limb symmetry by Saunders (1968)
10.1128/jvi.62.3.1008-1015.1988 / J. Virol / Development of avian sarcoma and leukosis virus-based vector-packaging cell lines by Stoker (1988)
10.1016/0092-8674(94)90175-9 / Cell / Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs by Tabata (1994)
10.1038/254199a0 / Nature / Positional signalling and specification of digits in chick limb morphogenesis by Tickle (1975)
10.1038/296564a0 / Nature / Local application of retinoic acid to the limb bud mimics the action of the polarizing region by Tickle (1982)
10.1016/0012-1606(85)90348-3 / Dev. Biol / A quantitative analysis of the effect of all-trans retinoic acid on the pattern of chick wing development by Tickle (1985)
{'key': '2025021322573873000_DEVELOP_122_6_1821C42', 'first-page': '478', 'article-title': 'Vertebrate limb development', 'volume': '5', 'author': 'Tickle', 'year': '1995', 'journal-title': 'Curr. Biol'} / Curr. Biol / Vertebrate limb development by Tickle (1995)
10.1038/350081a0 / Nature / Conversion by retinoic acid of anterior cells into ZPA cells in the chick wing bud by Wanek (1991)
10.1126/science.3201241 / Science / Novel regulators of bone formation: molecular clones and activities by Wozney (1988)
10.1016/0092-8674(95)90297-X / Cell / Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning by Yang (1995)

Dates

Type	When
Created	4 years, 4 months ago (April 25, 2021, 10:43 p.m.)
Deposited	6 months, 1 week ago (Feb. 13, 2025, 5:57 p.m.)
Indexed	1 month ago (July 26, 2025, 4:46 a.m.)
Issued	29 years, 2 months ago (June 1, 1996)
Published	29 years, 2 months ago (June 1, 1996)
Published Online	29 years, 2 months ago (June 1, 1996)
Published Print	29 years, 2 months ago (June 1, 1996)

Funders 0

None

BibTeX

@article{Duprez_1996, title={Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb}, volume={122}, ISSN={1477-9129}, url={http://dx.doi.org/10.1242/dev.122.6.1821}, DOI={10.1242/dev.122.6.1821}, number={6}, journal={Development}, publisher={The Company of Biologists}, author={Duprez, Delphine M. and Kostakopoulou, Konstadina and Francis-West, Philippa H. and Tickle, Cheryll and Brickell, Paul M.}, year={1996}, month=jun, pages={1821–1828} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        26
      ]
    ],
    "date-time": "2025-07-26T08:46:31Z",
    "timestamp": 1753519591262,
    "version": "3.37.0"
  },
  "reference-count": 45,
  "publisher": "The Company of Biologists",
  "issue": "6",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            1996,
            6,
            1
          ]
        ],
        "date-time": "1996-06-01T00:00:00Z",
        "timestamp": 833587200000
      },
      "content-version": "vor",
      "delay-in-days": 0,
      "URL": "http://www.biologists.com/user-licence-1-1/"
    }
  ],
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        1996,
        6,
        1
      ]
    ]
  },
  "abstract": "<jats:title>ABSTRACT</jats:title>\n               <jats:p>Bone morphogenetic protein-2 (BMP-2) has been implicated in the polarizing region signalling pathway, which specifies pattern across the antero-posterior of the developing vertebrate limb. Retinoic acid and Sonic Hedgehog (SHH) can act as polarizing signals; when applied anteriorly in the limb bud, they induce mirror-image digit duplications and ectopic Bmp-2 expression in anterior mesenchyme. In addition, the two signals can activate Fgf-4 expression in anterior ridge and HoxD expression in anterior mesenchyme. We tested the role of BMP-2 in this signalling cascade by ectopically expressing human BMP-2 (hBMP-2) at the anterior margin of the early wing bud using a replication defective retroviral vector, and found that ectopic expression of Fgf-4 was induced in the anterior part of the apical ectodermal ridge, followed later by ectopic expression of Hoxd-11 and Hoxd-13 in anterior mesenchyme. This suggests that BMP-2 is involved in regulating Fgf-4 and HoxD gene expression in the normal limb bud. Ectopically expressed hBMP-2 also induced duplication of digit 2 and bifurcation of digit 3, but could not produce the mirror-image digit duplications obtained with SHH-expressing cells. These results suggest that BMP-2 may be involved primarily in maintenance of the ridge, and in the link between patterning and outgrowth of the limb bud.</jats:p>",
  "DOI": "10.1242/dev.122.6.1821",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2021,
        4,
        26
      ]
    ],
    "date-time": "2021-04-26T02:43:34Z",
    "timestamp": 1619405014000
  },
  "page": "1821-1828",
  "source": "Crossref",
  "is-referenced-by-count": 113,
  "title": "Activation of <i>Fgf-4</i> and <i>HoxD</i> gene expression by BMP-2 expressing cells in the developing chick limb",
  "prefix": "10.1242",
  "volume": "122",
  "author": [
    {
      "given": "Delphine M.",
      "family": "Duprez",
      "sequence": "first",
      "affiliation": [
        {
          "name": "1 Medical Molecular Biology Unit, Department of Molecular Pathology"
        }
      ]
    },
    {
      "given": "Konstadina",
      "family": "Kostakopoulou",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "1 Medical Molecular Biology Unit, Department of Molecular Pathology"
        },
        {
          "name": "University College London Medical School 2 Department of Anatomy and Developmental Biology , , The Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Philippa H.",
      "family": "Francis-West",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "1 Medical Molecular Biology Unit, Department of Molecular Pathology"
        },
        {
          "name": "University College London Medical School 2 Department of Anatomy and Developmental Biology , , The Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Cheryll",
      "family": "Tickle",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "University College London Medical School 2 Department of Anatomy and Developmental Biology , , The Windeyer Building, Cleveland Street, London W1P 6DB, UK"
        }
      ]
    },
    {
      "given": "Paul M.",
      "family": "Brickell",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "1 Medical Molecular Biology Unit, Department of Molecular Pathology"
        }
      ]
    }
  ],
  "member": "237",
  "published-online": {
    "date-parts": [
      [
        1996,
        6,
        1
      ]
    ]
  },
  "reference": [
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C1",
      "doi-asserted-by": "publisher",
      "first-page": "69",
      "DOI": "10.1016/0012-1606(77)90110-5",
      "article-title": "Stage related capacity for limb chondrogenesis in cell culture",
      "volume": "60",
      "author": "Ahrens",
      "year": "1977",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C2",
      "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": "2025021322573873000_DEVELOP_122_6_1821C3",
      "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": "2025021322573873000_DEVELOP_122_6_1821C4",
      "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": "2025021322573873000_DEVELOP_122_6_1821C5",
      "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": "2025021322573873000_DEVELOP_122_6_1821C6",
      "doi-asserted-by": "publisher",
      "first-page": "187",
      "DOI": "10.1016/0925-4773(93)90035-V",
      "article-title": "Ectopic expression of genes during chicken limb pattern formation using replication defective retroviral vectors",
      "volume": "43",
      "author": "Pompa",
      "year": "1993",
      "journal-title": "Mech. Dev"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C7",
      "doi-asserted-by": "publisher",
      "first-page": "431",
      "DOI": "10.1016/0092-8674(93)90378-4",
      "article-title": "Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs",
      "volume": "75",
      "author": "Doll\u00e9",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C8",
      "doi-asserted-by": "crossref",
      "first-page": "53",
      "DOI": "10.1515/9783110861082-009",
      "article-title": "Role of the ectoderm in limb development of normal and mutant mouse (Disorganisation, Pupoid Foetus) and fowl (talpid3) embryos",
      "volume-title": "In Teratology of the Limbs",
      "author": "Ede",
      "year": "1980"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C9",
      "doi-asserted-by": "publisher",
      "first-page": "1",
      "DOI": "10.1242/dev.121.1.1",
      "article-title": "Positional signaling by hedgehog in Drosophila imaginal disc development",
      "volume": "121",
      "author": "Felsenfeld",
      "year": "1995",
      "journal-title": "Development"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C10",
      "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": "2025021322573873000_DEVELOP_122_6_1821C11",
      "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": "2025021322573873000_DEVELOP_122_6_1821C12",
      "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": "2025021322573873000_DEVELOP_122_6_1821C13",
      "doi-asserted-by": "publisher",
      "first-page": "4329",
      "DOI": "10.1242/dev.121.12.4329",
      "article-title": "Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme",
      "volume": "121",
      "author": "Hardy",
      "year": "1995",
      "journal-title": "Development"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C14",
      "doi-asserted-by": "publisher",
      "first-page": "913",
      "DOI": "10.1016/0092-8674(93)90535-X",
      "article-title": "The TGF\u03b2 homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina",
      "volume": "75",
      "author": "Heberlein",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C15",
      "doi-asserted-by": "publisher",
      "first-page": "3004",
      "DOI": "10.1128/jvi.61.10.3004-3012.1987",
      "article-title": "Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors",
      "volume": "61",
      "author": "Hughes",
      "year": "1987",
      "journal-title": "J. Virol"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C16",
      "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": "2025021322573873000_DEVELOP_122_6_1821C17",
      "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": "2025021322573873000_DEVELOP_122_6_1821C18",
      "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": "2025021322573873000_DEVELOP_122_6_1821C19",
      "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 signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud",
      "volume": "79",
      "author": "Laufer",
      "year": "1994",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C20",
      "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": "2025021322573873000_DEVELOP_122_6_1821C21",
      "doi-asserted-by": "publisher",
      "first-page": "2808",
      "DOI": "10.1101/gad.9.22.2808",
      "article-title": "BMP 7 is an inducer of nephrogenesis and is also required for eye development and skeletal patterning",
      "volume": "9",
      "author": "Luo",
      "year": "1995",
      "journal-title": "Genes Dev"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C22",
      "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": "2025021322573873000_DEVELOP_122_6_1821C23",
      "doi-asserted-by": "publisher",
      "first-page": "547",
      "DOI": "10.1016/0092-8674(94)90520-7",
      "article-title": "The ins and outs of fibroblast growth factors",
      "volume": "78",
      "author": "Mason",
      "year": "1994",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C24",
      "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": "2025021322573873000_DEVELOP_122_6_1821C25",
      "doi-asserted-by": "publisher",
      "first-page": "617",
      "DOI": "10.1006/dbio.1995.1053",
      "article-title": "FGF can induce outgrowth of somatic mesoderm both inside and outside of limb-forming regions",
      "volume": "167",
      "author": "Mima",
      "year": "1995",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C26",
      "doi-asserted-by": "publisher",
      "first-page": "236",
      "DOI": "10.1038/358236a0",
      "article-title": "Targeted mis-expression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations",
      "volume": "358",
      "author": "Morgan",
      "year": "1992",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C27",
      "first-page": "181",
      "article-title": "Hox genes and growth: early and late roles in limb bud morphogenesis",
      "volume-title": "Development (supplement)",
      "author": "Morgan",
      "year": "1994"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C28",
      "doi-asserted-by": "publisher",
      "first-page": "68",
      "DOI": "10.1038/361068a0",
      "article-title": "FGF-4 and BMP-2 have opposite effects on limb growth",
      "volume": "361",
      "author": "Niswander",
      "year": "1993",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C29",
      "doi-asserted-by": "publisher",
      "first-page": "579",
      "DOI": "10.1016/0092-8674(93)90391-3",
      "article-title": "FGF-4 replaces the apical actodermal ridge and directs outgrowth and patterning of the limb",
      "volume": "75",
      "author": "Niswander",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C30",
      "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": "2025021322573873000_DEVELOP_122_6_1821C31",
      "doi-asserted-by": "publisher",
      "first-page": "83",
      "DOI": "10.1038/350083a0",
      "article-title": "Retinoic acid induces polarizing activity but is unlikely to be a morphogen in the chick limb bud",
      "volume": "350",
      "author": "Noji",
      "year": "1991",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C32",
      "doi-asserted-by": "publisher",
      "first-page": "350",
      "DOI": "10.1038/374350a0",
      "article-title": "Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb",
      "volume": "374",
      "author": "Parr",
      "year": "1995",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C33",
      "doi-asserted-by": "publisher",
      "first-page": "1401",
      "DOI": "10.1016/0092-8674(93)90626-2",
      "article-title": "Sonic hedgehog mediates the polarizing activity of the ZPA",
      "volume": "75",
      "author": "Riddle",
      "year": "1993",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C34",
      "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": "2025021322573873000_DEVELOP_122_6_1821C35",
      "doi-asserted-by": "publisher",
      "first-page": "103",
      "DOI": "10.1002/aja.1002000203",
      "article-title": "Transforming growth factor-\u03b2 and bone morphogenetic protein-2 act by distinct mechanisms to promote chick limb cartilage differentiation in vitro",
      "volume": "200",
      "author": "Roark",
      "year": "1994",
      "journal-title": "Dev. Dynam"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C36",
      "first-page": "78",
      "article-title": "Ectodermal-mesenchymal interactions in the origin of limb symmetry",
      "volume-title": "In Epithelial-Mesenchymal Interactions",
      "author": "Saunders",
      "year": "1968"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C37",
      "doi-asserted-by": "publisher",
      "first-page": "1008",
      "DOI": "10.1128/jvi.62.3.1008-1015.1988",
      "article-title": "Development of avian sarcoma and leukosis virus-based vector-packaging cell lines",
      "volume": "62",
      "author": "Stoker",
      "year": "1988",
      "journal-title": "J. Virol"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C38",
      "doi-asserted-by": "publisher",
      "first-page": "89",
      "DOI": "10.1016/0092-8674(94)90175-9",
      "article-title": "Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs",
      "volume": "76",
      "author": "Tabata",
      "year": "1994",
      "journal-title": "Cell"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C39",
      "doi-asserted-by": "publisher",
      "first-page": "199",
      "DOI": "10.1038/254199a0",
      "article-title": "Positional signalling and specification of digits in chick limb morphogenesis",
      "volume": "254",
      "author": "Tickle",
      "year": "1975",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C40",
      "doi-asserted-by": "publisher",
      "first-page": "564",
      "DOI": "10.1038/296564a0",
      "article-title": "Local application of retinoic acid to the limb bud mimics the action of the polarizing region",
      "volume": "296",
      "author": "Tickle",
      "year": "1982",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C41",
      "doi-asserted-by": "publisher",
      "first-page": "82",
      "DOI": "10.1016/0012-1606(85)90348-3",
      "article-title": "A quantitative analysis of the effect of all-trans retinoic acid on the pattern of chick wing development",
      "volume": "109",
      "author": "Tickle",
      "year": "1985",
      "journal-title": "Dev. Biol"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C42",
      "first-page": "478",
      "article-title": "Vertebrate limb development",
      "volume": "5",
      "author": "Tickle",
      "year": "1995",
      "journal-title": "Curr. Biol"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C43",
      "doi-asserted-by": "publisher",
      "first-page": "81",
      "DOI": "10.1038/350081a0",
      "article-title": "Conversion by retinoic acid of anterior cells into ZPA cells in the chick wing bud",
      "volume": "350",
      "author": "Wanek",
      "year": "1991",
      "journal-title": "Nature"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C44",
      "doi-asserted-by": "publisher",
      "first-page": "1528",
      "DOI": "10.1126/science.3201241",
      "article-title": "Novel regulators of bone formation: molecular clones and activities",
      "volume": "242",
      "author": "Wozney",
      "year": "1988",
      "journal-title": "Science"
    },
    {
      "key": "2025021322573873000_DEVELOP_122_6_1821C45",
      "doi-asserted-by": "publisher",
      "first-page": "939",
      "DOI": "10.1016/0092-8674(95)90297-X",
      "article-title": "Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning",
      "volume": "80",
      "author": "Yang",
      "year": "1995",
      "journal-title": "Cell"
    }
  ],
  "container-title": "Development",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://journals.biologists.com/dev/article-pdf/122/6/1821/3070011/develop_122_6_1821.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "https://journals.biologists.com/dev/article-pdf/122/6/1821/3070011/develop_122_6_1821.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2025,
        2,
        13
      ]
    ],
    "date-time": "2025-02-13T22:57:53Z",
    "timestamp": 1739487473000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://journals.biologists.com/dev/article/122/6/1821/39186/Activation-of-Fgf-4-and-HoxD-gene-expression-by"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1996,
        6,
        1
      ]
    ]
  },
  "references-count": 45,
  "journal-issue": {
    "issue": "6",
    "published-print": {
      "date-parts": [
        [
          1996,
          6,
          1
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1242/dev.122.6.1821",
  "relation": {},
  "ISSN": [
    "0950-1991",
    "1477-9129"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        1996,
        6,
        1
      ]
    ]
  }
}