Collagen XVIII regulates extracellular matrix integrity in the developing nephrons and impacts nephron progenitor cell behavior.

• Collagen XVIII isoforms differ in their expression during nephrogenesis, where the short isoform is expressed in the early phases of nephron development and the two longer forms are detected only in more mature stage of nephrogenesis. • The lack of collagen XVIII isoforms leads to distinct congenital ultrastructural defects of nephrons. • Collagen XVIII deficient fetuses show decreased nephron progenitor cell numbers and changes in nephron progenitors' cell cycle progression. • Altered Sall1 expression and increased macrophage influx in the developing kidney might play a role in the detected defects in the nephron progenitor cell population in collagen XVIII deficient fetuses. Renal development is a complex process in which two major processes, tubular branching and nephron development, regulate each other reciprocally. Our previous findings have indicated that collagen XVIII (ColXVIII), an extracellular matrix protein, affects the renal branching morphogenesis. We investigate here the role of ColXVIII in nephron formation and the behavior of nephron progenitor cells (NPCs) using isoform-specific ColXVIII knockout mice. The results show that the short ColXVIII isoform predominates in the early epithelialized nephron structures whereas the two longer isoforms are expressed only in the later phases of glomerular formation. Meanwhile, electron microscopy showed that the ColXVIII mutant embryonic kidneys have ultrastructural defects at least from embryonic day 16.5 onwards. Similar structural defects had previously been observed in adult ColXVIII-deficient mice, indicating a congenital origin. The lack of ColXVIII led to a reduced NPC population in which changes in NPC proliferation and maintenance and in macrophage influx were perceived to play a role. The changes in NPC behavior in turn led to notably reduced overall nephron formation. In conclusion, the results show that ColXVIII has multiple roles in renal development, both in ureteric branching and in NPC behavior. [ABSTRACT FROM AUTHOR]