http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-louie a video presentation of this article.

Video 1Case presentation including cross-sectional imaging, percutaneous cholangiogram, percutaneous cholangioscopy, and histopathology of cholangioscopy-directed biopsies.

The signaling pathway mediated by BMPs plays an essential role during development as well as the maintenance of homeostasis in adult. Aberrant activation or inactivation of BMP signaling can lead to developmental defects and various human disorders. To fine-tune its activity, BMP signaling is regulated both positively and negatively by extrinsic and intrinsic regulatory factors that modulate binding of ligand to the receptors, and the activity of receptors and their dedicated signal transducers, the Smad proteins. Upon BMP binding to the receptor complex, Smad proteins translocate to the nucleus and modulate gene expression transcriptionally by directly associating with the promoter region of target genes, or post-transcriptionally through modulation of microRNA (miRNA) synthesis. In this study, we demonstrate that BMP signaling down-regulates transcription of the miRNA-302∼367 gene cluster. We show that the type II BMP receptor (BMPRII) is a novel target of miR-302. Upon overexpression, miR-302 targets a partially complementary sequence localized in the 3'-untranslated region (UTR) of BMPRII transcripts and leads to destabilization of the transcripts and down-regulation of BMP signaling. We propose that the negative regulatory loop of BMP4-miR-302-BMPRII is a potential mechanism for the maintenance and fine-tuning of the BMP signaling pathway in various systems.

It is widely accepted that different forms of stress activate a common target, p53, yet different outcomes are triggered in a stress-specific manner. For example, activation of p53 by genotoxic agents, such as camptothecin (CPT), triggers apoptosis, while non-genotoxic activation of p53 by Nutlin-3 (Nut3) leads to cell-cycle arrest without significant apoptosis. Such stimulus-specific responses are attributed to differential transcriptional activation of various promoters by p53. In this study, we demonstrate that CPT, but not Nut3, induces miR-203, which downregulates anti-apoptotic bcl-w and promotes cell death in a p53-dependent manner. We find that acetylation of K120 in the DNA-binding domain of p53 augments its association with the Drosha microprocessor and promotes nuclear primary miRNA processing. Knockdown of human orthologue of Males absent On the First (hMOF), the acetyltransferase that targets K120 in p53, abolishes induction of miR-203 and cell death mediated by CPT. Thus, this study reveals that p53 acetylation at K120 plays a critical role in the regulation of the Drosha microprocessor and that post-transcriptional regulation of gene expression by p53 via miRNAs plays a role in determining stress-specific cellular outcomes.

Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.

Hematopoietic stem and progenitor cells arise from the vascular endothelium of the dorsal aorta and subsequently switch niche to the fetal liver through unknown mechanisms. Here we report that vascular endothelium-specific deletion of mouse Drosha (Drosha ^cKO), an enzyme essential for microRNA biogenesis, leads to anemia and death. A similar number of hematopoietic stem and progenitor cells emerge from Drosha-deficient and control vascular endothelium, but Drosha ^cKO-derived hematopoietic stem and progenitor cells accumulate in the dorsal aorta and fail to colonize the fetal liver. Depletion of the let-7 family of microRNAs is a primary cause of this defect, as it leads to activation of leukotriene B4 signaling and induction of the α4β1 integrin cell adhesion complex in hematopoietic stem and progenitor cells. Inhibition of leukotriene B4 or integrin rescues maturation and migration of Drosha ^cKO hematopoietic stem and progenitor cells to the fetal liver, while it hampers hematopoiesis in wild-type animals. Our study uncovers a previously undefined role of innate leukotriene B4 signaling as a gatekeeper of the hematopoietic niche transition.Hematopoietic stem and progenitor cells are generated first from the vascular endothelium of the dorsal aorta and then the fetal liver but what regulates this switch is unknown. Here, the authors show that changing miRNA biogenesis and leukotriene B4 signaling in mice modulates this switch in the niche.