Mesenchymal Hox6 function is required for pancreatic endocrine cell differentiation

Abstract

Despite significant advances in our understanding of pancreatic endocrine cell development, the function of the pancreatic mesodermal niche in this process is poorly understood. Here we report a novel role for mouse Hox6 genes in pancreatic organogenesis. Hox6 genes are expressed exclusively in the mesoderm of the developing pancreas. Genetic loss of all three Hox6 paralogs (Hoxa6, Hoxb6 and Hoxc6) leads to a dramatic loss of endoderm-derived endocrine cells, including insulin-secreting β-cells, and to mild delays and disruptions in pancreatic branching and exocrine differentiation. Ngn3-expressing pan-endocrine progenitor cells are specified normally in Hox6 mutant pancreata, but fail to mature into hormone-producing cells. Reduced expression of Wnt5a is observed in mutant pancreatic mesenchyme, leading to subsequent loss of expression of the crucial Wnt inhibitors Sfrp3 and Dkk1 in endocrine progenitor cells. These results reveal a key role for Hox6 genes in establishing Wnt mesenchymal-epithelial crosstalk in pancreatic development.

Natural products against renin-angiotensin system for antifibrosis therapy

“…Mutations in Wnt5b and transcription factor 7-like 2 are observed in type II diabetes [159]. Downregulated Wnt5a, FZD-related proteins and Dkk1 are discovered in mutant pancreatic mesenchyme [160] and Wnt/β-catenin pathway is activated in intervertebral disc cells [161], which is highly consistant with previous findings. Additionally, overexpression of Wnt1 and Wnt5a or the inhibitory activities of Wnt-C59 on Wnts are all evidence of the critical role of the Wnt/β-catenin pathway in myocardial fibrosis progression and myofibroblast formation [162].…”

Pancreas organogenesis: The interplay between surrounding microenvironment(s) and epithelium-intrinsic factors

“…The mechanisms by which these mesenchymal signals are coordinated and integrated to stimulate epithelial progenitor proliferation and differentiation to produce functional pancreatic cells remain elusive. Also, whether is the developing pancreatic mesenchyme a homogenous tissue or composed of different mesenchymal cell populations, resembling distinct "cellular niches", like in the haematopoietic and nervous system, lungs and skin, is unclear (Crane et al, 2017;Kfoury and Scadden, 2015;Lattanzi et al, 2015;Roberts et al, 2017;Zepp et al, 2017 , Nkx3.2 and Hoxa6, Hoxb6 and Hoxc6 (Ahlgren et al, 1997;Asayesh et al, 2006;Hecksher-Sørensen et al, 2004;Landsman et al, 2011;Larsen et al, 2015). Isl1 is expressed in both pancreatic epithelium and mesenchyme and is required for dorsal mesenchyme formation (Ahlgren et al, 1997).…”

Hox genes in the adult skeleton: Novel functions beyond embryonic development

“…Similar to the pattern observed in the skeleton, the function of a paralogous group of genes is regionally restricted and is colinear with their chromosomal arrangement. Hox3 paralogous group genes function in the thymus, Hox5 genes in the lung, Hox6 genes in the pancreas, and Hox10 and Hox11 genes in the kidney and the spleen (Roberts et al, ; Manley and Capecchi, ; Wellik et al, ; Yallowitz et al, ; Boucherat et al, ; Chojnowski et al, ; Hrycaj et al, ; Larsen et al, ). In the adult, tissue resident fibroblasts/mesenchymal cells can be isolated from all of these organs (and more), and maintained Hox expression has also been noted (Yamamoto et al, ; Takahashi et al, ; da Silva Meirelles et al, ; Crisan et al, ; Worthley et al, ).…”