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 language | English |
|---|---|
| Pages (from-to) | 27235-27243 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 270 |
| Issue number | 45 |
| DOIs | |
| Publication status | Published - 01-01-1995 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
}
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 journal › Article
TY - JOUR
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.
PY - 1995/1/1
Y1 - 1995/1/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=0028858477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028858477&partnerID=8YFLogxK
U2 - 10.1074/jbc.270.45.27235
DO - 10.1074/jbc.270.45.27235
M3 - Article
VL - 270
SP - 27235
EP - 27243
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 45
ER -