Abstract
Inversion of embryonic turning (inv) cystic mice develop multiple renal cysts and are a model for type II nephronophthisis (NPHP2). The defect of planar cell polarity (PCP) by oriented cell division was proposed as the underlying cellular phenotype, while abnormal cell proliferation and apoptosis occur in some polycystic kidney disease models. However, how these cystogenic phenotypes are linked and what is most critical for cystogenesis remain largely unknown. In particular, in early cortical cytogenesis in the inv mutant cystic model, it remains uncertain whether the increased proliferation index results from changes in cell cycle length or cell fate determination. To address tubular cell kinetics, doubling time and total number of tubular cells, as well as amount of genomic DNA (gDNA), were measured in mutant and normal control kidneys. Despite a significantly higher bromodeoxyuridine (BrdU)-proliferation index in the mutant, total tubular cell number and doubling time were unaffected. Unexpectedly, the mutant had tubular cell loss, characterized by a temporal decrease in tubular cells incorporating 5-ethynyl-2´-deoxyuridine (EdU) and significantly increased nuclear debris. Based on current data we established a new multi-population shift model in postnatal renal development, indicating that a few restricted tubular cell populations contribute to cortical tubular formation. As in the inv mutant phenotype, the model simulation revealed a large population of tubular cells with rapid cell cycling and tubular cell loss. The proposed cellular kinetics suggest not only the underlying mechanism of the inv mutant phenotype but also a possible renal homeostatic mechanism for tubule formation.
Highlights
Inversion of embryonic turning mutant mice develop situs inversus, jaundice and polycystic kidneys, with most mutants dying before postnatal day (P) 7 [1, 2]
The proliferation index was significantly increased in the invDC cystic model (Table 1 and S1 Fig), overall tubular growth in the postnatal cortex showed a Tubular cell kinetics in early cortical cystogenesis was unveiled by a new multi-population shift model
Taken together, considering that total cell numbers were no different in control and mutant kidneys (Fig 1), these results suggested that tubular cell loss likely occurred in renal cystogenesis, preventing an overall increase in cell number
Summary
Inversion of embryonic turning (inv) mutant mice develop situs inversus, jaundice and polycystic kidneys, with most mutants dying before postnatal day (P) 7 [1, 2]. The cystic phenotype, including tubular dilatation, was shown to be similar in mice and humans [4]. The C-terminal domain of inv is poorly conserved in mice and humans, while the N-terminal domain with ankyrin. Tubular cell kinetics in early cortical cystogenesis was unveiled by a new multi-population shift model repeats is highly conserved [5]. Introduction of a modified inv gene, lacking the C-terminus (invDC), rescued all inv phenotypes except for cystic kidneys [7, 8]. Because the invDC mutant survives longer than inv mutant, the invDC model is useful for investigating renal cystogenesis, excluding its other associated abnormalities
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