Person:

Kumar, Deepak

Pax7 is a key regulator of skeletal muscle stem cells and is required along with Pax3 to generate skeletal muscle precursors. We have identified a collection of genes induced by either Pax3 or Pax7 in C2C12 muscle cells. Two notable Pax3/7 targets are the inhibitory helix-loop-helix (HLH) proteins inhibitor of DNA binding (Id) 2 and Id3, both of which are coordinately expressed with Pax7 in quiescent satellite cells and are induced in quiescent C2C12 myogenic cells after ectopic expression of either Pax3 or Pax7. Ectopic Pax7 activates expression of a luciferase reporter driven by the Id3 promoter, and maximal induction of this reporter requires a conserved Pax7 binding site located upstream of the Id3 gene. Chromatin immunoprecipitation indicated that Pax7 is bound upstream of the Id3 promoter in quiescent satellite cells. In addition, short hairpin RNA-mediated knockdown of Pax7 expression in cultured satellite cells coordinately decreased both Id2 and Id3 expression. Together, these findings indicate that Id3 is a direct transcriptional target for Pax7 in quiescent satellite cells, and they suggest that Pax7 acts to block premature differentiation of quiescent satellite cells by inducing the expression of Id2 and Id3, which in turn may act to block either the precocious induction of myogenic basic (b)HLH proteins, the activity of myogenic bHLH proteins, or both.

The amyloid-β peptide (Aβ) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting Aβ is an antimicrobial peptide. Here we provide the first in vivo evidence showing high Aβ production protects against fungal and bacterial infections in mouse and nematode AD models. In Aβ-null mouse models low Aβ production is associated with attenuated resistance to infection. Regarding mechanism, we show Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, is necessary for the antimicrobial activities of the peptide. Soluble Aβ oligomers bind microbial cell walls, developing protofibrils inhibit pathogen host cell adhesion, and, finally, proteaseresistant β-amyloid fibrils agglutinate and entrap the invading microbes. We also show that infection of 5XFAD mouse brain with S. Typhimurium bacteria rapidly seeds and dramatically accelerates β-amyloid deposition, which closely co-localizes with invading bacteria. Collectively, our findings raise the intriguing possibility that β-amyloid plays a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.