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| Status |
Public on Dec 31, 2017 |
| Title |
Haploinsufficiency for SIX2 increases nephron progenitor proliferation leading to elevated branching and nephron number |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The regulation of final nephron number in the kidney is poorly understood. However, cessation of nephron formation occurs when the self-renewing nephron progenitor population commits to differentiation. Transcription factors within this progenitor population, such as SIX2, are assumed to control expression of genes promoting self-renewal such that homozygous Six2 deletion results in premature commitment and an early halt to kidney development. In contrast, Six2 heterozygotes were assumed to be unaffected. Using quantitative morphometry, we demonstrate here a paradoxical 18% increase in ureteric branching and final nephron number in Six2 heterozygotes, despite evidence for reduced levels of SIX2 protein and transcript. This is accompanied by a clear shift in nephron progenitor identity with a distinct subset of progenitor genes, including Cited1 and Meox1, downregulated, while others were unaffected. The net result was an increase in nephron progenitor proliferation, as assessed by elevated EDU labelling, an increase in MYC protein and transcriptional upregulation of MYC target genes. Reducing proliferation by introducing Six2 heterozygosity onto the Fgf20-/- background resulted in premature differentiation of the progenitor population. Overall, this data demonstrates a unique dose response of the nephron progenitors to the level of SIX2 protein in which the role of SIX2 in progenitor proliferation versus self-renewal is separable.
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| Overall design |
Gene expression profiling of 33 embryonic whole kidney samples for Six2 wild type, heterozygous and knock out mice at 11.5 and 15.5 dpc.
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| Contributor(s) |
Phipson B |
| Citation missing |
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| |
| Submission date |
Aug 29, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Belinda Phipson |
| Organization name |
WEHI
|
| Department |
Bioinformatics
|
| Lab |
Phipson
|
| Street address |
1G Royal Parade
|
| City |
Parkville |
| State/province |
VIC |
| ZIP/Postal code |
3052 |
| Country |
Australia |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (33)
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| Relations |
| BioProject |
PRJNA400562 |
| SRA |
SRP116375 |
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