Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176 RXXR 179 /S 180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.Online Mendelian Inheritance in Man no. 193100) is characterized by low serum phosphate concentrations due to isolated renal phosphate wasting, inappropriately normal or low serum 1,25(OH) 2 vitamin D (1,25D) concentrations, and rickets/osteomalacia and fracture (1). Heterozygous missense mutations in the fibroblast growth factor-23 (FGF23) gene cause ADHR (2). These mutations replace the arginine (R) residues at positions 176 or 179 with glutamine (Q) or tryptophan (W) within a 176 RXXR 179 / S 180 subtilisin-like proprotein convertase (SPC) site that separates the conserved FGF-like N-terminal domain from the variable Cterminal tail (2-4). Acting through the coreceptor α-Klotho (5) and a fibroblast growth factor receptor (FGFR) (5, 6), FGF23 reduces renal phosphate reabsorption through down-regulation of the sodium phosphate cotransporters NPT2a and NPT2c and suppresses kidney 1,25(OH) 2 vitamin D production by inhibiting and increasing vitamin D 1α-hydroxylase (Cyp27b1) and 24-hydroxylase expression (Cyp24), respectively (7). Compared with WT Fgf23 protein, ADHR-mutant FGF23 shows increased but not complete resistance to SPC proteolytic cleavage (3, 4). When expressed in mammalian cells, the R176Q-, R179Q-, and R179W-FGF23 proteins are secreted primarily as the full-length (32-kDa) polypeptide, in contrast to the full-length and cleavage products (20 and 12 kDa) typically observed for WT FGF23 (3). This proteolytic event inactivates the mature FGF23 polypeptide, as full-length FGF23, but not N-terminal fragments (residues 25-179) or C-terminal fragments (residues 180-251), reduces serum phosphate concentrations when injected into rodents (4).The ADHR...

Background:The role of SREBP-1 in regulating carbohydrate metabolism is unclear. Results: Silencing SREBP-1 reduced glycogen buildup and expression of genes involved in glycogen synthesis as well as gluconeogenesis. Conclusion: SREBP-1 is needed to regulate carbohydrate metabolism during the fed state. Thus, its depletion does not improve insulin resistance. Significance: This report provides a novel function for SREBP-1.

MicroRNA (miRNA) are short non-coding RNA molecules that regulate multiple cellular processes, including development, cell differentiation, proliferation and death. Nevertheless, little is known on whether miRNA control the same gene networks in different tissues. miR-709 is an abundant miRNA expressed ubiquitously. Through transcriptome analysis, we have identified targets of miR-709 in hepatocytes. miR-709 represses genes implicated in cytoskeleton organization, extracellular matrix attachment, and fatty acid metabolism. Remarkably, none of the previously identified targets in non-hepatic tissues are silenced by miR-709 in hepatocytes, even though several of these genes are abundantly expressed in liver. In addition, miR-709 is upregulated in hepatocellular carcinoma, suggesting it participates in the genetic reprogramming that takes place during cell division, when cytoskeleton remodeling requires substantial changes in gene expression. In summary, the present study shows that miR-709 does not repress the same pool of genes in separate cell types. These results underscore the need for validating gene targets in every tissue a miRNA is expressed.

We genetically characterize an unusual hybrid incompatibility phenotype manifest in F1 offspring of crosses between two populations of Tribolium castaneum. Hybrid larvae cease development at the third larval instar, persisting as ‘perpetually immature larvae’ thereafter. Although unable to produce viable adult hybrid offspring with one another, each population produces abundant, fertile hybrids with other populations, indicating a recent origin of the incompatibility and facilitating genetic studies. We mapped the paternal component of the hybrid phenotype to a single region, which exhibits two characteristics common to hybrid incompatibility: marker transmission ratio distortion within crosses and elevated genetic divergence between populations. The incompatible variation and an elevation in between‐population genetic divergence is associated with a region containing the T. castaneum ecdysone receptor homologue, a major regulatory switch, controlling larval moults, pupation and metamorphosis. This contributes to understanding the genetics of speciation in the Coleoptera, one of the most speciose of all arthropod taxa.