Pluto Bioinformatics

GSE126551: Lats1/2 suppress NFkB and aberrant EMT initiation to permit pancreas progenitor differentiation

Bulk RNA sequencing

The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues and its underlying molecular targets are poorly understood. Our study shows that Hippo suppresses NFB signaling in pancreatic progenitors to permit cell differentiation and developmental progression. We found that pancreas-specific Lats1/2 kinase deletion (Lats1/2PanKO) from mouse progenitor epithelia results in failure to differentiate 3 key pancreatic lineages: acinar, ductal, and endocrine. We performed an unbiased transcriptome analysis to query the differentiation defects in Lats1/2PanKO. This analysis revealed increased NFB activator expression, including the pantetheinase Vanin1 (Vnn1). Through in vivo and ex vivo studies, we show that VNN1 activates a detrimental cascade of processes in Lats1/2PanKO epithelium, whereby 1) NFB activation and 2) initiation of epithelial-to-mesenchymal transition (EMT) together override normal differentiation. We show that exogenous stimulation of VNN1 or NFB can also trigger this cascade in WT pancreatic progenitors. These findings show that pancreas development requires active suppression of NFB by LATS1/2 kinases to restrain a cell-autonomous transcriptional program and thereby allow for differentiation. SOURCE: Ondine Cleaver (ondine.cleaver@utsouthwestern.edu) - UT Southwestern Medical Center