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 a1(IV)2a2(IV) for basement membrane assembly
and embryonic development, we generated a null allele of
the Col4a1/2 locus in mice, thereby ablating both a-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.