Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice

K. Kobayashi, S. Morita, H. Sawada, T. Mizuguchi, K. Yamada, I. Nagatsu, Tadayoshi Hata, Y. Watanabe, K. Fujita, T. Nagatsu

Research output: Contribution to journalArticle

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Abstract

Tyrosine 3-hydroxylase (TH, EC 1.14.16.2) catalyzes the first and rate- limiting step of the catecholamine biosynthetic pathway in the nervous and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination. Mice heterozygous for the TH mutation were apparently normal. In these mice, TH activity in the embryos and adult tissues was less than 50% of the wild-type values, but the catecholamine level was decreased only moderately in the developing animals and was maintained normally at adulthood, suggesting the presence of a regulatory mechanism for ensuring the proper catecholamine level during animal development. In contrast, the homozygous mutant mice died at a late stage of embryonic development or shortly after birth. Both TH mRNA and enzyme activity were lacking in the homozygous mutants, which thus explained the severe depletion of catecholamines. These changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels. Analysis of electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice that may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme. These results indicate that TH is essential for survival of the animals during the late gestational development and after birth.

Original languageEnglish
Pages (from-to)27235-27243
Number of pages9
JournalJournal of Biological Chemistry
Volume270
Issue number45
DOIs
Publication statusPublished - 01-01-1995

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Tyrosine 3-Monooxygenase
Catecholamines
Animals
Parturition
Mutation
Endocrine System
Homologous Recombination
Biosynthetic Pathways
Enzyme activity
Enzymes
Bradycardia
Mixed Function Oxygenases
Stem cells
Electrocardiography
Transgenes
Human Activities
Nervous System
Embryonic Development
Embryonic Structures
Tissue

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kobayashi, K. ; Morita, S. ; Sawada, H. ; Mizuguchi, T. ; Yamada, K. ; Nagatsu, I. ; Hata, Tadayoshi ; Watanabe, Y. ; Fujita, K. ; Nagatsu, T. / Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 45. pp. 27235-27243.
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abstract = "Tyrosine 3-hydroxylase (TH, EC 1.14.16.2) catalyzes the first and rate- limiting step of the catecholamine biosynthetic pathway in the nervous and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination. Mice heterozygous for the TH mutation were apparently normal. In these mice, TH activity in the embryos and adult tissues was less than 50{\%} of the wild-type values, but the catecholamine level was decreased only moderately in the developing animals and was maintained normally at adulthood, suggesting the presence of a regulatory mechanism for ensuring the proper catecholamine level during animal development. In contrast, the homozygous mutant mice died at a late stage of embryonic development or shortly after birth. Both TH mRNA and enzyme activity were lacking in the homozygous mutants, which thus explained the severe depletion of catecholamines. These changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels. Analysis of electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice that may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme. These results indicate that TH is essential for survival of the animals during the late gestational development and after birth.",
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Kobayashi, K, Morita, S, Sawada, H, Mizuguchi, T, Yamada, K, Nagatsu, I, Hata, T, Watanabe, Y, Fujita, K & Nagatsu, T 1995, 'Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice', Journal of Biological Chemistry, vol. 270, no. 45, pp. 27235-27243. https://doi.org/10.1074/jbc.270.45.27235

Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. / Kobayashi, K.; Morita, S.; Sawada, H.; Mizuguchi, T.; Yamada, K.; Nagatsu, I.; Hata, Tadayoshi; Watanabe, Y.; Fujita, K.; Nagatsu, T.

In: Journal of Biological Chemistry, Vol. 270, No. 45, 01.01.1995, p. 27235-27243.

Research output: Contribution to journalArticle

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T1 - Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice

AU - Kobayashi, K.

AU - Morita, S.

AU - Sawada, H.

AU - Mizuguchi, T.

AU - Yamada, K.

AU - Nagatsu, I.

AU - Hata, Tadayoshi

AU - Watanabe, Y.

AU - Fujita, K.

AU - Nagatsu, T.

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AB - Tyrosine 3-hydroxylase (TH, EC 1.14.16.2) catalyzes the first and rate- limiting step of the catecholamine biosynthetic pathway in the nervous and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination. Mice heterozygous for the TH mutation were apparently normal. In these mice, TH activity in the embryos and adult tissues was less than 50% of the wild-type values, but the catecholamine level was decreased only moderately in the developing animals and was maintained normally at adulthood, suggesting the presence of a regulatory mechanism for ensuring the proper catecholamine level during animal development. In contrast, the homozygous mutant mice died at a late stage of embryonic development or shortly after birth. Both TH mRNA and enzyme activity were lacking in the homozygous mutants, which thus explained the severe depletion of catecholamines. These changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels. Analysis of electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice that may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme. These results indicate that TH is essential for survival of the animals during the late gestational development and after birth.

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