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1.  The Transcription Factor Myt3 Acts as a Pro-Survival Factor in β-cells 
PLoS ONE  2012;7(12):e51501.
Aims/Hypothesis
We previously identified the transcription factor Myt3 as specifically expressed in pancreatic islets. Here, we sought to determine the expression and regulation of Myt3 in islets and to determine its significance in regulating islet function and survival.
Methods
Myt3 expression was determined in embryonic pancreas and adult islets by qPCR and immunohistochemistry. ChIP-seq, ChIP-qPCR and luciferase assays were used to evaluate regulation of Myt3 expression. Suppression of Myt3 was used to evaluate gene expression, insulin secretion and apoptosis in islets.
Results
We show that Myt3 is the most abundant MYT family member in adult islets and that it is expressed in all the major endocrine cell types in the pancreas after E18.5. We demonstrate that Myt3 expression is directly regulated by Foxa2, Pdx1, and Neurod1, which are critical to normal β-cell development and function, and that Ngn3 induces Myt3 expression through alterations in the Myt3 promoter chromatin state. Further, we show that Myt3 expression is sensitive to both glucose and cytokine exposure. Of specific interest, suppressing Myt3 expression reduces insulin content and increases β-cell apoptosis, at least in part, due to reduced Pdx1, Mafa, Il-6, Bcl-xl, c-Iap2 and Igfr1 levels, while over-expression of Myt3 protects islets from cytokine induced apoptosis.
Conclusion/Interpretation
We have identified Myt3 as a novel transcriptional regulator with a critical role in β-cell survival. These data are an important step in clarifying the regulatory networks responsible for β-cell survival, and point to Myt3 as a potential therapeutic target for improving functional β-cell mass.
doi:10.1371/journal.pone.0051501
PMCID: PMC3517555  PMID: 23236509
3.  Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy  
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1–NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are “ciliopathies”. Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
doi:10.1172/JCI40076
PMCID: PMC2827951  PMID: 20179356

Results 1-3 (3)