Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric
type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV)
collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of
type IV collagen have been associated with diverse biological processes including defects in molecular filtration in
Alport syndrome, cell differentiation in hereditary
leiomyomatosis, and autoimmunity in
Goodpasture syndrome; however, the transcriptional and developmental regulation of
type IV collagen expression is unknown.
Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain
transcription factor. Some patients have
nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV
collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV)
collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV)
collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and
nephrosis in NPS.