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Genes to Cells (2010) 15, 77-89. doi:10.1111/j.1365-2443.2009.01366.x
© 2010 Blackwell Publishing or its licensors
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Indispensable function for embryogenesis, expression and regulation of the nonspecific form of the 5-aminolevulinate synthase gene in mouse

 Satoshi Okano1, Lingyun Zhou1,2, Toshimasa Kusaka1, Kazuhide Shibata1, Kazuhiro Shimizu1, Xu Gao1,2, Yuko Kikuchi3, Yoshiyuki Togashi1, Tomonori Hosoya1,3, Satoru Takahashi3, Osamu Nakajima1,* and Masayuki Yamamoto3,4,*

1 Research Laboratory for Molecular Genetics, Yamagata University, Yamagata 990-9585, Japan
2 Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150086, China
3 Center for Tsukuba Advanced Research Alliance and JST-ERATO Environmental Response Project, University of Tsukuba, Tsukuba 305-8577, Japan
4 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan

The first step of heme biosynthesis in animals is catalyzed by 5-aminolevulinate synthase (ALAS), which controls heme supply in various tissues. To clarify the roles that the nonspecific isoform of ALAS (ALAS-N) plays in vivo, we prepared a green fluorescent protein (GFP) knock-in mouse line in which the Alas1 gene (encoding ALAS-N) is replaced with a gfp gene. We found that mice bearing a homozygous knock-in allele (Alas1GFP/GFP) were lethal by embryonic day 8.5, demonstrating that ALAS-N is essential for early embryogenesis. Fluorescence microscopic and flow cytometric analyses of heterozygous mouse (Alas1+/GFP) tissues showed that the Alas1 expression level differs substantially in tissues; Alas1 is highly expressed in testis Leydig cells, exocrine glands (including submandibular and parotid glands), endocrine glands (such as adrenal and thyroid glands) and hematopoietic lineage cells (including neutrophils and eosinophils). Quantitative analyses of GFP mRNA and ALAS-N mRNA in various tissues of Alas1+/GFP mice suggested that the destabilization of ALAS-N mRNA was not uniform in the various tissues. These results thus lay bare that elaborate control of the endogenous heme supply operates in various mouse tissues through regulation of the ALAS-N expression level and that this control is essential for heme homeostasis in animals.

Communicated by: Kohei Miyazono

* Correspondence:nakajima{at}med.id.yamagata-u.ac.jp or masi{at}mail.tains.tohoku.ac.jp






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