Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice
Identifieur interne : 000113 ( Ncbi/Merge ); précédent : 000112; suivant : 000114Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice
Auteurs : Minoru Kobayashi [France] ; Ciro Iaccarino [France] ; Adolfo Saiardi [France] ; Valérie Heidt [France] ; Yuri Bozzi [France] ; Roberto Picetti [France] ; Carmine Vitale [France] ; Heiner Westphal [États-Unis] ; John Drago [Australie] ; Emiliana Borrelli [France]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2004.
Abstract
Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative/synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1/D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (
Url:
DOI: 10.1073/pnas.0402028101
PubMed: 15272078
PubMed Central: 509223
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<author><name sortKey="Vitale, Carmine" sort="Vitale, Carmine" uniqKey="Vitale C" first="Carmine" last="Vitale">Carmine Vitale</name>
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<affiliation wicri:level="4"><nlm:aff id="N0x9679798.0x9852960">Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia</nlm:aff>
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<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
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<author><name sortKey="Borrelli, Emiliana" sort="Borrelli, Emiliana" uniqKey="Borrelli E" first="Emiliana" last="Borrelli">Emiliana Borrelli</name>
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<front><div type="abstract" xml:lang="en"><p>Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative/synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1/D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (<italic>D1r</italic>
<sup>-/-</sup>
;<italic>D2r</italic>
<sup>+/-</sup>
) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in <italic>D1r</italic>
/<italic>D2r</italic>
compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of <italic>D1r</italic>
ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the single-gene ablation studies.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id>
<journal-id journal-id-type="publisher-id">pnas</journal-id>
<journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title>
<issn pub-type="ppub">0027-8424</issn>
<issn pub-type="epub">1091-6490</issn>
<publisher><publisher-name>National Academy of Sciences</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">15272078</article-id>
<article-id pub-id-type="pmc">509223</article-id>
<article-id pub-id-type="publisher-id">10111465</article-id>
<article-id pub-id-type="doi">10.1073/pnas.0402028101</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject>
<subj-group><subject>Neuroscience</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kobayashi</surname>
<given-names>Minoru</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
<xref ref-type="fn" rid="fn1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Iaccarino</surname>
<given-names>Ciro</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saiardi</surname>
<given-names>Adolfo</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heidt</surname>
<given-names>Valérie</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bozzi</surname>
<given-names>Yuri</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
<xref ref-type="fn" rid="fn2">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Picetti</surname>
<given-names>Roberto</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vitale</surname>
<given-names>Carmine</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Westphal</surname>
<given-names>Heiner</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">§</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Drago</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">¶</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Borrelli</surname>
<given-names>Emiliana</given-names>
</name>
<xref ref-type="aff" rid="N0x9679798.0x9852960">*</xref>
<xref ref-type="corresp" rid="cor1">∥</xref>
</contrib>
</contrib-group>
<aff id="N0x9679798.0x9852960"><label>*</label>
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, 67404 Illkirch, France;<label>§</label>
Laboratory of Mammalian Genes and Development, National Institutes of Health, Bethesda, MD 20892; and<label>¶</label>
Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia</aff>
<author-notes><fn id="cor1"><label>∥</label>
<p> To whom correspondence should be addressed. E-mail: <email>eb@igbmc.u-strasbg.fr</email>
. </p>
</fn>
<fn id="fn1"><label>†</label>
<p>Present address: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Nagaizumi-cho, Shizuoka 411-8731, Japan.</p>
</fn>
<fn id="fn2"><label>‡</label>
<p>Present address: Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Pisa 56100, Italy.</p>
</fn>
<fn><p>Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved June 21, 2004</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>3</day>
<month>8</month>
<year>2004</year>
</pub-date>
<pub-date pub-type="epub"><day>22</day>
<month>7</month>
<year>2004</year>
</pub-date>
<volume>101</volume>
<issue>31</issue>
<fpage>11465</fpage>
<lpage>11470</lpage>
<history><date date-type="received"><day>23</day>
<month>3</month>
<year>2004</year>
</date>
</history>
<copyright-statement>Copyright © 2004, The National Academy of Sciences</copyright-statement>
<copyright-year>2004</copyright-year>
<abstract><p>Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative/synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1/D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (<italic>D1r</italic>
<sup>-/-</sup>
;<italic>D2r</italic>
<sup>+/-</sup>
) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in <italic>D1r</italic>
/<italic>D2r</italic>
compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of <italic>D1r</italic>
ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the single-gene ablation studies.</p>
</abstract>
<kwd-group><kwd>knockout mice</kwd>
<kwd>motor function</kwd>
<kwd>feeding behavior</kwd>
<kwd>gastrointestinal system</kwd>
</kwd-group>
</article-meta>
<notes><fn-group><fn><p>This paper was submitted directly (Track II) to the PNAS office.</p>
</fn>
<fn><p>Abbreviations: DA, dopamine; DKO, double knockout; TH, tyrosine hydroxylase; Enk, enkephalin; SP, substance P; Dyn, dynorphin; NPY, neuropeptide Y; AGRP, agouti-related protein; GI, gastrointestinal.</p>
</fn>
</fn-group>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>États-Unis</li>
</country>
<region><li>Alsace (région administrative)</li>
<li>Grand Est</li>
<li>Maryland</li>
<li>Victoria (État)</li>
</region>
<settlement><li>Illkirch</li>
<li>Melbourne</li>
</settlement>
<orgName><li>Université de Melbourne</li>
</orgName>
</list>
<tree><country name="France"><region name="Grand Est"><name sortKey="Kobayashi, Minoru" sort="Kobayashi, Minoru" uniqKey="Kobayashi M" first="Minoru" last="Kobayashi">Minoru Kobayashi</name>
</region>
<name sortKey="Borrelli, Emiliana" sort="Borrelli, Emiliana" uniqKey="Borrelli E" first="Emiliana" last="Borrelli">Emiliana Borrelli</name>
<name sortKey="Bozzi, Yuri" sort="Bozzi, Yuri" uniqKey="Bozzi Y" first="Yuri" last="Bozzi">Yuri Bozzi</name>
<name sortKey="Heidt, Valerie" sort="Heidt, Valerie" uniqKey="Heidt V" first="Valérie" last="Heidt">Valérie Heidt</name>
<name sortKey="Iaccarino, Ciro" sort="Iaccarino, Ciro" uniqKey="Iaccarino C" first="Ciro" last="Iaccarino">Ciro Iaccarino</name>
<name sortKey="Picetti, Roberto" sort="Picetti, Roberto" uniqKey="Picetti R" first="Roberto" last="Picetti">Roberto Picetti</name>
<name sortKey="Saiardi, Adolfo" sort="Saiardi, Adolfo" uniqKey="Saiardi A" first="Adolfo" last="Saiardi">Adolfo Saiardi</name>
<name sortKey="Vitale, Carmine" sort="Vitale, Carmine" uniqKey="Vitale C" first="Carmine" last="Vitale">Carmine Vitale</name>
</country>
<country name="États-Unis"><region name="Maryland"><name sortKey="Westphal, Heiner" sort="Westphal, Heiner" uniqKey="Westphal H" first="Heiner" last="Westphal">Heiner Westphal</name>
</region>
</country>
<country name="Australie"><region name="Victoria (État)"><name sortKey="Drago, John" sort="Drago, John" uniqKey="Drago J" first="John" last="Drago">John Drago</name>
</region>
</country>
</tree>
</affiliations>
</record>
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