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First published online 3 March 2004
doi: 10.1242/dev.01037
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1 Department of Experimental Medicine I, University Erlangen-Nürnberg,
91054 Erlangen, Germany
2 Department of Ophthalmology, University Erlangen-Nürnberg, 91054
Erlangen, Germany
3 Department of Molecular Biology and Biochemistry, Okayama University Medical
School, Okayama 700, Japan
4 Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences,
University of Manchester, Manchester M13 9PT, UK
* Author for correspondence (e-mail: epoeschl{at}molmed.uni-erlangen.de)
Accepted 12 December 2003
Basement membranes are specialized extracellular matrices consisting of
tissue-specific organizations of multiple matrix molecules and serve as
structural barriers as well as substrates for cellular interactions. The
network of collagen IV is thought to define the scaffold integrating other
components such as, laminins, nidogens or perlecan, into highly organized
supramolecular architectures. To analyze the functional roles of the major
collagen IV isoform
1(IV)2
2(IV) for basement membrane
assembly and embryonic development, we generated a null allele of the
Col4a1/2 locus in mice, thereby ablating both
-chains.
Unexpectedly, embryos developed up to E9.5 at the expected Mendelian ratio and
showed a variable degree of growth retardation. Basement membrane proteins
were deposited and assembled at expected sites in mutant embryos, indicating
that this isoform is dispensable for matrix deposition and assembly during
early development. However, lethality occurred between E10.5-E11.5, because of
structural deficiencies in the basement membranes and finally by failure of
the integrity of Reichert's membrane. These data demonstrate for the first
time that collagen IV is fundamental for the maintenance of integrity and
function of basement membranes under conditions of increasing mechanical
demands, but dispensable for deposition and initial assembly of components.
Taken together with other basement membrane protein knockouts, these data
suggest that laminin is sufficient for basement membrane-like matrices during
early development, but at later stages the specific composition of components
including collagen IV defines integrity, stability and functionality.
Key words: Collagen IV, Col4a1, Col4a2, Knockout, Basement membrane, Development
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