Combined Sry-Related HMG Box-4 (SOX4) and SOX11 Signaling in Nephron Progenitor Cells Is Required for Normal Renal Development In Vivo

Title:
Combined Sry-Related HMG Box-4 (SOX4) and SOX11 signaling is
required for normal renal development in vivo

Sushant Gavhale,
Michel Arsenault, Blanca Esparza-Nino, Ashley Patriquen, Glenda M Wright, Sunny
Hartwig.

Congenital
anomalies of the kidney and urinary tract (CAKUT) are the
most common cause of childhood end-stage renal disease. Members of the Sry-Related
HMG Box-C (SOX-C) subfamily of nuclear
transcription factors, including Sox4 and the closely-related Sox11, play
overlapping and essential roles in controlling progenitor stem cell fate during
organogenesis in vivo. We have previously demonstrated that both Sox4 and Sox11 are
expressed in multiple progenitor cell populations during murine kidney development.
Genetic ablation of Sox4 in nephron progenitor cells (Sox4^nephron-
mice) results in CAKUT and end stage renal failure by 5 months in
vivo, demonstrating
an essential and non-overlapping role for Sox4 in kidney development in
vivo. Here we present our preliminary findings following conditional
ablation of both Sox4 and Sox11 in the nephron progenitor lineage
(Sox4/11^nephron-). In contrast to Sox4^nephron-mice,
Sox4/11^nephron-animals die neonatally by postnatal day 1 (P1);
lethality is associated with renal insufficiency (n=30) of variable
presentation including bilateral renal agenesis (n=4), ulilateral renal
agenesis (n=2), severe hypoglomerularopathy (n=7), and cystic renal dysplasia(n=4).
Characterization of adult compound Sox4/Sox11 heterozygotes is currently
underway, along with quantitative assessment of the embryonic phenotypes of Sox4/Sox11^nephron-kidneys, including quantitative assessment of renal morphogenesis, nephron
progenitor proliferation, apoptosis and differentiation, nephrogenesis and
marker analysis. Collectively, our work will define a
novel Sox4/11 signaling pathway that controls normal kidney development in
vivo.

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Acknowledgment:
Funding from CIHR, Kidney Research Scientist Core Education and
National Training (KRESCENT) Program and the Kidney Foundation of Canada (Sunny
Hartwig�s grant) are gratefully acknowledged.

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