Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid
Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12–13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicu...
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| Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 2006-08, Vol.20 (8), p.1796-1809 |
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| creator | Kusakabe, Takashi Kawaguchi, Akio Hoshi, Nobuo Kawaguchi, Rumi Hoshi, Sayuri Kimura, Shioko |
| description | Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12–13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl);TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl);TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl);TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl);TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids. |
| doi_str_mv | 10.1210/me.2005-0327 |
| format | Article |
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To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl);TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl);TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl);TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl);TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/me.2005-0327</identifier><identifier>PMID: 16601074</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Adenovirus ; Alleles ; Animals ; Cell Differentiation ; Gene Deletion ; Gene Expression ; Integrases - metabolism ; Male ; Mice ; Mice, Knockout ; Nuclear Proteins - deficiency ; Nuclear Proteins - genetics ; Nuclear Proteins - physiology ; Organ Specificity ; RNA, Messenger - metabolism ; Spheroids, Cellular - physiology ; Thyroid Gland - anatomy & histology ; Thyroid Gland - metabolism ; Thyroid Gland - physiology ; Thyroid Nuclear Factor 1 ; Transcription Factors - deficiency ; Transcription Factors - genetics ; Transcription Factors - physiology</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2006-08, Vol.20 (8), p.1796-1809</ispartof><rights>Copyright © 2006 by The Endocrine Society 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c555t-ffb4e06664e473263c8d80f0e6e68ee2e050314d3e76dd06b0a3bdba3df7dee43</citedby><cites>FETCH-LOGICAL-c555t-ffb4e06664e473263c8d80f0e6e68ee2e050314d3e76dd06b0a3bdba3df7dee43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16601074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kusakabe, Takashi</creatorcontrib><creatorcontrib>Kawaguchi, Akio</creatorcontrib><creatorcontrib>Hoshi, Nobuo</creatorcontrib><creatorcontrib>Kawaguchi, Rumi</creatorcontrib><creatorcontrib>Hoshi, Sayuri</creatorcontrib><creatorcontrib>Kimura, Shioko</creatorcontrib><title>Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12–13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl);TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl);TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl);TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl);TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.</description><subject>Adenovirus</subject><subject>Alleles</subject><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Gene Deletion</subject><subject>Gene Expression</subject><subject>Integrases - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Nuclear Proteins - deficiency</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - physiology</subject><subject>Organ Specificity</subject><subject>RNA, Messenger - metabolism</subject><subject>Spheroids, Cellular - physiology</subject><subject>Thyroid Gland - anatomy & histology</subject><subject>Thyroid Gland - metabolism</subject><subject>Thyroid Gland - physiology</subject><subject>Thyroid Nuclear Factor 1</subject><subject>Transcription Factors - deficiency</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - physiology</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1u1DAURi0EokNhxxp5BRsytRPHcTZIpbRQUSiCIrGzHPu6cTWxU9tB6nPwwiSaiB8JvPHinnv8yR9CTynZ0pKSowG2JSF1QaqyuYc2tGWsaFva3EcbIoQohCDtAXqU0g0hlNWCPkQHlHNCScM26MdVfxeDM8WXEbSzTuNT3yuvIRavnTfOX-NPMWRw_ujj-2_lluLzhD_D7eQiGGxDxLkH_EE5n8EvezhYfBkNLOPjqHuXQecpAlbe4LPJ6-yCX6Bl742zdiZ9dirP_JrlMXpg1S7Bk_U-RF_PTq9O3hUXl2_PT44vCl3XdS6s7RgQzjkD1lQlr7QwglgCHLgAKIHUpKLMVNBwYwjviKo606nK2MYAsOoQvdp7x6kbwOg5R1Q7OUY3qHgng3Ly74l3vbwO32VZC8FKMQuer4IYbidIWQ4uadjtlIcwJUnbZj6UzODLPahjSCmC_fUIJXJpUQ4glxbl0uKMP_sz2G94rW0GXuyBMI3_UxWrqtqT4E3Q0XkYI6Qkb8IU_fy5_w7wEzAHuJI</recordid><startdate>20060801</startdate><enddate>20060801</enddate><creator>Kusakabe, Takashi</creator><creator>Kawaguchi, Akio</creator><creator>Hoshi, Nobuo</creator><creator>Kawaguchi, Rumi</creator><creator>Hoshi, Sayuri</creator><creator>Kimura, Shioko</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20060801</creationdate><title>Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid</title><author>Kusakabe, Takashi ; Kawaguchi, Akio ; Hoshi, Nobuo ; Kawaguchi, Rumi ; Hoshi, Sayuri ; Kimura, Shioko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c555t-ffb4e06664e473263c8d80f0e6e68ee2e050314d3e76dd06b0a3bdba3df7dee43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adenovirus</topic><topic>Alleles</topic><topic>Animals</topic><topic>Cell Differentiation</topic><topic>Gene Deletion</topic><topic>Gene Expression</topic><topic>Integrases - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Nuclear Proteins - deficiency</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - physiology</topic><topic>Organ Specificity</topic><topic>RNA, Messenger - metabolism</topic><topic>Spheroids, Cellular - physiology</topic><topic>Thyroid Gland - anatomy & histology</topic><topic>Thyroid Gland - metabolism</topic><topic>Thyroid Gland - physiology</topic><topic>Thyroid Nuclear Factor 1</topic><topic>Transcription Factors - deficiency</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kusakabe, Takashi</creatorcontrib><creatorcontrib>Kawaguchi, Akio</creatorcontrib><creatorcontrib>Hoshi, Nobuo</creatorcontrib><creatorcontrib>Kawaguchi, Rumi</creatorcontrib><creatorcontrib>Hoshi, Sayuri</creatorcontrib><creatorcontrib>Kimura, Shioko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kusakabe, Takashi</au><au>Kawaguchi, Akio</au><au>Hoshi, Nobuo</au><au>Kawaguchi, Rumi</au><au>Hoshi, Sayuri</au><au>Kimura, Shioko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2006-08-01</date><risdate>2006</risdate><volume>20</volume><issue>8</issue><spage>1796</spage><epage>1809</epage><pages>1796-1809</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12–13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl);TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl);TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl);TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl);TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>16601074</pmid><doi>10.1210/me.2005-0327</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenovirus Alleles Animals Cell Differentiation Gene Deletion Gene Expression Integrases - metabolism Male Mice Mice, Knockout Nuclear Proteins - deficiency Nuclear Proteins - genetics Nuclear Proteins - physiology Organ Specificity RNA, Messenger - metabolism Spheroids, Cellular - physiology Thyroid Gland - anatomy & histology Thyroid Gland - metabolism Thyroid Gland - physiology Thyroid Nuclear Factor 1 Transcription Factors - deficiency Transcription Factors - genetics Transcription Factors - physiology |
| title | Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid |
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