Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development

Abstract

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 α1(IV)2α2(IV) for basement membrane assembly and embryonic development, we generated a null allele of the Col4a1/2 locus in mice, thereby ablating both α-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.

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

“…Radial glial endfeet provide anchorage at the meningeal basement membrane of the pia mater to support the highly extended morphology of radial fibres in the developing brain. Disruption of this attachment causes defects in cortical lamination, such as in mice with genetic defects in integrins, ILK, FAK, and ECM components (Graus-Porta et al, 2001;Halfter et al, 2002;Beggs et al, 2003;Poschl et al, 2004;Niewmierzycka et al, 2005). SPARC could potentially act to anchor radial glial endfeet, either by modulating the stability of focal adhesions via integrin-mediated FAK and ILK signaling (Shi et al, 2007), or alternatively by the assembly and maintenance of ECM components in the basement membrane (Yan et al, 2003).…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

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Fetal intracerebral hemorrhage and COL4A1 mutation: promise and uncertainty

“…The use of ultrasound is valuable in assessing surgical outcomes after TVM procedures 3,9 . In the present patient, ultrasound identified a vaginal hematoma that compressed and distorted the lower urinary tract as the probable etiology for voiding dysfunction.…”