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J. Biol. Chem., Vol. 282, Issue 4, 2512-2519, January 26, 2007

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Loss of Assembly of the Main Basement Membrane Collagen, Type IV, but Not Fibril-forming Collagens and Embryonic Death in Collagen Prolyl 4-Hydroxylase I Null Mice^*

Tiina Holster^¶, Outi Pakkanen^¶, Raija Soininen^¶, Raija Sormunen^||, Minna Nokelainen^¶1, Kari I. Kivirikko^¶, and Johanna Myllyharju^¶2

From the Collagen Research Unit, Biocenter Oulu, ^¶Department of Medical Biochemistry and Molecular Biology, and ^||Department of Pathology, University of Oulu, 90014 Oulu, Finland

Collagen prolyl 4-hydroxylases (C-P4Hs) catalyze the formation of the 4-hydroxyproline residues that are essential for the generation of triple helical collagen molecules. The vertebrate C-P4Hs I, II, and III are [(I)]₂₂, [(II)]₂₂, and [(III)]₂₂ tetramers with identical subunits. We generated mice with targeted inactivation of the P4ha1 gene encoding the catalytic subunit of C-P4H I to analyze its specific functions. The null mice died after E10.5, showing an overall developmental delay and a dilated endoplasmic reticulum in their cells. The capillary walls were frequently ruptured, but the capillary density remained unchanged. The C-P4H activity level in the null embryos and fibroblasts cultured from them was 20% of that in the wild type, being evidently due to the other two isoenzymes. Collagen IV immunofluorescence was almost absent in the basement membranes of the null embryos, and electron microscopy revealed disrupted basement membranes, while immunoelectron microscopy showed a lack of collagen IV in them. The amount of soluble collagen IV was increased in the null embryos and cultured null fibroblasts, indicating a lack of assembly of collagen IV molecules into insoluble structures, probably due to their underhydroxylation and hence abnormal conformation. In contrast, the null embryos had collagen I and III fibrils with a typical cross-striation pattern but slightly increased diameters, and the null fibroblasts secreted fibril-forming collagens, although less efficiently than wild-type cells. The primary cause of death of the null embryos was thus most likely an abnormal assembly of collagen IV.

Received for publication, July 12, 2006 , and in revised form, November 22, 2006.

^* This work was supported by Health Science Council Grants 200471 and 202469 and Finnish Centre of Excellence Programme 2000–2005 Grant 44843 of the Academy of Finland, and the S. Juselius Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Ark Therapeutics, FIN-70210 Kuopio, Finland.

² To whom correspondence should be addressed: P. O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland. Tel.: 358-8-537-5740; Fax: 358-8-537-5811; E-mail: johanna.myllyharju{at}oulu.fi.

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