Lipid malabsorption from altered hormonal signaling changes early gut microbial responses.

Infants with congenital diarrheal disorders caused by enteroendocrine cell dysgenesis, or the loss of intestinal endocrine cells, causes severe malabsorptive diarrhea, though the mechanism is not fully understood. The transcription factor "aristaless-related homeobox" (Arx) is specifically expressed in intestinal endocrine cells. This study seeks to characterize the early malabsorptive phenotype of mice deficient for Arx using cell-type specific gene ablation in Villin-Cre; ArxloxP/Y ( Arxint) mice. In neonatal mice, the loss of intestinal Arx caused the loss of intestinal hormones, such as cholecystokinin, secretin, neurotensin, glucose-dependent insulinotropic peptide, glucagon-like peptide (GLP)-1 and GLP-2 but also upregulation of somatostatin. Arxint mice exhibited steatorrhea with the loss of lipid transport in duodenal enterocytes, upregulation of lysozyme-positive Paneth cells, and a secondary increase in antimicrobial peptides, specifically Reg3ß. When the epithelium from Arxint mice was cultured ex vivo into enteroids, however, the Reg3ß upregulation was lost under the sterile conditions. Thus, Arx is required for the appropriate lineage allocation of multiple enteroendocrine subtypes. We concluded that altered hormonal signaling caused by Arx deficiency results in lipid malabsorption, premature Paneth cell differentiation, and an inflammatory response, including neutrophilic infiltrates and a microbiota-triggered upregulation of Reg3ß. NEW & NOTEWORTHY The enteroendocrine transcription factor aristaless-related homeobox (Arx) plays a key role in lineage specification. Changes in hormonal expression mediated by Arx lead to lipid malabsorption and premature Paneth cell development. Furthermore, global profiling of whole intestine from Arx-deficient mice revealed significant upregulation of antimicrobial peptides. This antimicrobial response in Arx-deficient animals is lost under sterile culture conditions of enteroids.

Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins.

Vascular morphogenesis requires a delicate gradient of Notch signaling controlled, in part, by the distribution of ligands (Dll4 and Jagged1). How Jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here, we show that Jag1 mRNA is a direct target of zinc-finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we find robustly induced by vascular endothelial growth factor (VEGF). Endothelial cells lacking ZFP36 display high levels of JAG1 and increase angiogenic sprouting in vitro. Furthermore, mice lacking Zfp36 in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front alters NOTCH1 signaling, increasing the number of tip cells, a phenotype that is rescued by imposing haploinsufficiency of Jag1. Our findings reveal an important feedforward loop whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.