Ascl2 Acts as an R-spondin/Wnt-Responsive Switch to Control Stemness in Intestinal Crypts

The Wnt signaling pathway controls stem cell identity in the intestinal epithelium and in many other adult organs. The transcription factor Ascl2 (a Wnt target gene) is a master regulator of intestinal stem cell identity. It is unclear how the continuous Wnt gradient along the crypt axis is translated into discrete expression of Ascl2 and discrete specification of stem cells at crypt bottoms. We show that (1) Ascl2 is regulated in a direct autoactivatory loop, leading to a distinct on/off expression pattern, and (2) Wnt/R-spondin can activate this regulatory loop. This mechanism interprets the Wnt levels in the intestinal crypt and translates the continuous Wnt signal into a discrete Ascl2 "on'' or "off'' decision. In turn, Ascl2, together with beta-catenin/Tcf, activates the genes fundamental to the stem cell state. In this manner, Ascl2 forms a transcriptional switch that is both Wnt responsive and Wnt dependent to define stem cell identity

Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities

Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV. In nine patients with MS, atrial effective refractory period and local activation times (ATs) were determined during stimulation before and after PTMV, with up to four decapolar catheters (LA and RA). Eight patients with ventricular pre-excitation served as controls. ATs at basic cycle length were similar before and after PTMV. With stimulation from either atrium, they were about 45 ms in the ipsilateral atrium and about 115 ms in the contralateral atrium. With premature stimulation, ATs increased dramatically. The shortest ATs were found in the RA with RA stimulation (78 +/- 9 and 80 +/- 6 ns, before and after PTMV). PTMV caused a shortening in LA-ATs (following LA stimulation) from 118 +/- 14 to 82 +/- 5 ms (before and after; P <0.05). Asymmetry in conduction properties was therefore normalized by PTMV. PTMV led to a decrease in RA-ATs (following LA stimulation) from 196 +/- 11 to 174 +/- 13 ms (P <0.02). In addition, following RA stimulation, the dispersion in ATs in the LA decreased significantly by PTMV (from 66 +/- 10 to 34 +/- 7 ms; P <0.02). MS is associated with LA conduction delay, increased LA dispersion of conduction, and conduction asymmetry. These changes are immediately reversible by PTMV