Islet architecture in adult mice is actively maintained by Robo2 expression in ß cells.

A fundamental question in developmental biology is whether tissue architectures formed during development are set for life, or require continuous maintenance signals, and if so, what are those signals. The islets of Langerhans in the pancreas can serve as an elegant model tissue to answer these questions. Islets have a non-random spatial architecture, which is important to proper glucose homeostasis. Islet architecture forms during embryonic development, in a morphogenesis process partially involving expression of Roundabout (Robo) receptors in ß cells, and their ligand, Slit, in the surrounding mesenchyme. Whether islet architecture is set during development and remains passive in adulthood, or whether it requires active maintenance throughout life, has not been determined. Here we conditionally deleted Robo2 in ß cells of adult mice and observed their islet architecture following a two-month chase. We show that deleting Robo2 in adult ß cells causes significant loss of islet architecture without affecting ß cell identity, maturation, or stress, indicating that Robo2 plays a role in actively maintaining adult islet architecture. Understanding the factors required to maintain islet architecture, and thus optimize islet function, is important for developing future diabetes therapies.

Disrupted glucose homeostasis and glucagon and insulin secretion defects in Robo ßKO mice.

The axon guidance proteins, Roundabout (Robo) receptors play a critical role in morphogenesis of the islets of Langerhans. Mice with a ß cell-selective deletion of Robo (Robo ßKO), show severely disrupted spatial architecture of their islets, without defects in ß cell differentiation or maturity. We have recently shown that Robo ßKO mice have reduced synchronous glucose-stimulated ß cell calcium oscillations in their islets in vivo, likely disrupting their pulsatile insulin secretion. Here, we analyze whole-body metabolic regulation in Robo ßKO mice. We show that Robo ßKO mice have mild defects in glucose homeostasis, and altered glucagon and insulin secretion. However, we did not observe any severe whole-body glucoregulatory phenotype following the disruption of islet architecture in Robo ßKO. Our data suggest that islet architecture plays only a mild role in overall glucoregulation.

Ectopic CH60 mediates HAPLN1-induced cell survival signaling in multiple myeloma.

Multiple myeloma (MM), the second most common hematological malignancy, is generally considered incurable because of the development of drug resistance. We previously reported that hyaluronan and proteoglycan link protein 1 (HAPLN1) produced by stromal cells induces activation of NF-κB, a tumor-supportive transcription factor, and promotes drug resistance in MM cells. However, the identity of the cell surface receptor that detects HAPLN1 and thereby engenders pro-tumorigenic signaling in MM cells remains unknown. Here, we performed an unbiased cell surface biotinylation assay and identified chaperonin 60 (CH60) as the direct binding partner of HAPLN1 on MM cells. Cell surface CH60 specifically interacted with TLR4 to evoke HAPLN1-induced NF-κB signaling, transcription of anti-apoptotic genes, and drug resistance in MM cells. Collectively, our findings identify a cell surface CH60-TLR4 complex as a HAPLN1 receptor and a potential molecular target to overcome drug resistance in MM cells.

Vitamin D receptor absence does not enhance intestinal tumorigenesis in ApcPirc/+rats.

Epidemiological observations have prompted some to posit that elevated circulating vitamin D is responsible for reduced colon cancer in individuals residing near the equator. We have previously demonstrated that vitamin D has no effect on colon cancer in two rodent models of intestinal tumorigenesis. We have now extended this line of inquiry to ask whether ablation of vitamin D receptor (VDR) affects tumorigenesis. A VDR null rat was developed using Cas9-CRISPR technology, which allowed us to investigate whether 1,25(OH)D3 signaling through its receptor plays a role in intestinal tumorigenesis. Loss of VDR expression alone did not induce tumorigenesis, even in animals exposed to the inflammatory agent dextran sodium sulfate. These VDR-/- rats were then crossed with ApcPirc/+ rats, which are predisposed to the development of intestinal neoplasms. In combination with the Pirc/+ mutation, VDR loss did not enhance tumor multiplicity, growth, or progression in the colon or small intestine. This study demonstrates that the vitamin D receptor does not impact tumor development, and strongly supports previous findings that vitamin D itself does not play a role in colon cancer development or progression. Alternative explanations are needed for the original latitude hypothesis, as well as observational data in humans. This article has an associated First Person interview with the first author of the paper.

Axon Guidance Molecules in the Islets of Langerhans.

The islets of Langerhans, responsible for regulating blood glucose in vertebrates, are clusters of endocrine cells distributed throughout the exocrine pancreas. The spatial architecture of the different cell types within the islets controls cell-cell communication and impacts their ability to collectively regulate glucose. Islets rely on a range of chemotactic and adhesive cues to establish and manage intercellular relationships. Growing evidence indicates that axon guidance molecules such as Slit-Robo, Semaphorin-Neuropilin, Ephrin-Eph, and Netrins, influence endocrine progenitors' cell migration to establish correct architecture during islet morphogenesis, as well as directly regulating physical cell-cell communication in the mature islet to coordinate hormone secretion. In this mini-review, we discuss what is known and not yet known about how axon guidance molecules contribute to islet morphogenesis and function.