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Abstract: FR-PO926

Role of the Circadian Clock in the Timing of Branching Morphogenesis and Kidney Development

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

  • Sampogna, Rosemary V., Columbia University, New York, New York, United States
  • Dan, Hanbin, Columbia University, New York, New York, United States
  • Ruan, Thomas L., Columbia University Medical Center, New York, New York, United States
Background

Kidney development is guided by a complex array of molecular signals that guide precise arrangement of ~1 million nephrons. Developmental errors such as renal hypodysplasia are a leading cause of pediatric kidney failure. Extremely rapid and stereotypic branching of the ureteric tree during early kidney development gives rise to a stochastic branching pattern but with a much slower, controlled and constant tip doubling rate during the second half of development (JASN 2015;26(10):2414). We also found that iron deficiency has a profound effect on nephron number and branching morphogenesis. Because core circadian clock transcription factors bind heme, we hypothesized that this timer plays a role in the timing of kidney development.

Methods

We studied the roles of circadian clock regulators Clock and Bmal1 during kidney development by quantitating branching parameters in global knockout and in conditional mutants. We also measured continuous circadian clock gene expression in developing kidneys using luminescence microscopy. Mice also were mated for a 1-hour time period at "lights on" and subsequently RNASeq was performed from embryonic days 18.0 to 20.0 (E18.0 to E20.0) at exact 4-hour intervals to measure gene expression patterns. Relevant genes were mapped to specific nephron structures and compared to adult kidneys.

Results

Luminescence studies confirmed the activity of an autonomous peripheral clock in the developing kidney. Oscillatory expression of core clock genes became measurable by E18.5. Quantification of branching parameters showed decreased nephron number in Bmal1-/- kidneys at E14.5 and at E19.5 (mean glomerular number [SD] 664±103 vs. 956±84, p> 0.05). Moreover, when pregnancies were timed strictly, RNASeq analysis identified 6,949 transcripts with significant rhythmicity between days E18.0 and E20.0 (p<0.05). Many genes were kidney-specific and known to regulate cell cycle and core developmental processes.

Conclusion

While known to regulate renal processes in the adult, we found that circadian regulators also provide a critical timing mechanism during kidney development by controlling gene expression. These regulators are required during a critical developmental window. Investigation of circadian-regulated pathways may uncover new targets that can be exploited to prevent disease or aid kidney development.

Funding

  • NIDDK Support