Analysis of pyruvate dehydrogenase expression in embryonic mouse brain: localization and developmental regulation.

Brain malformations and neurological dysfunctions are often seen in pyruvate dehydrogenase (PDH) deficient patients. To understand these clinical presentations, we have analyzed the localization and developmental expression of PDH in the embryonic mouse nervous system. Immunostaining was performed to localize PDH E1 alpha protein. PDH activities were measured before and after activation. PDH E1 alpha mRNA levels were quantitated by reverse transcriptase-polymerase chain reaction. Abundant PDH E1 alpha protein was localized in the central nervous system and other neural tissues in embryos at embryonic day (E) 11 onwards. The PDH activity was very low in E9 brain and it increased continuously until the end of gestation. The proportion of active form of PDH increased significantly in E15 brain. Analysis of the PDH E1 alpha mRNA showed that only the X-linked form of the gene was transcribed. The overall mRNA level of E9 brain was approximately 93% of the adult value. It decreased gradually during embryogenesis. A large increase took place at the end of gestation. The mRNA level of PDH was approximately 100 times higher than that of the acetoacetyl-CoA thiolase gene. These results suggest that PDH E1 alpha transcripts of E9 brain are not translated at a high level. The appearance of PDH activity and its increase during E11 and E15 are mainly due to increased levels of translation and activation of PDH. Increased PDH activity at the end of gestation is attributed to an increase in transcription. Our data to a large extent explain pathological presentations in PDH E1 alpha deficient patients with congenital brain disorders.