Pancreatic ß-Cell-Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion.

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determine this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering homotypic fusion and vacuole protein sorting (HOPS) complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic ß-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule-regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in ß-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

Regeneration enhancers: Starting a journey to unravel regulatory events in tissue regeneration.

Regeneration, an ability to replace lost body parts, is widespread across animal species. While mammals poorly regenerate most tissues, teleost fish and urodele amphibians possess remarkable regenerative capacity. Earlier work demonstrated that genes driving regeneration are evolutionarily conserved, indicating that a key factor in diverse tissue regeneration is not the presence or absence of regeneration-driving genes but the mechanisms controlling activation of these genes after injury. Thus, understanding the regulatory events of tissue regeneration could provide the means for unlocking latent capacities for tissue regeneration. After injury, cells undergo extensive epigenetic changes to establish new transcriptional programs for tissue regeneration. Gene transcription in eukaryotes is a complicated process that requires specific interactions between trans-acting regulators and cis-regulatory DNA elements. Among cis-regulatory elements, enhancers are essential to control precise gene expression. Recently, multiple regeneration/injury-associated enhancers have been identified in several model organisms. In this review, we highlight recently discovered regeneration/injury enhancers and their specific characteristics. We also discuss how abnormal regulation of regeneration enhancers influences animal development and physiology. Investigation of regeneration enhancers potentially allows us to begin understanding the fundamental biology of tissue regeneration and inspires new solutions for manipulating regenerative ability.

Magnetic orientation in C. elegans relies on the integrity of the villi of the AFD magnetosensory neurons.

The magnetic field of the earth provides many organisms with sufficient information to successfully navigate through their environments. While evidence suggests the widespread use of this sensory modality across many taxa, it remains an understudied sensory modality. We have recently showed that the nematode C. elegans orients to earth-strength magnetic fields using the first pair of described magnetosensory neurons, AFDs. The AFD cells are a pair of ciliated sensory neurons crowned by fifty villi known to be implicated in temperature sensation. We investigated the potential importance of these subcellular structures for the performance of magnetic orientation. We show that ciliary integrity and villi number are essential for magnetic orientation. Mutants with impairments AFD cilia or villi structure failed to orient to magnetic fields. Similarly, C. elegans larvae possessing immature AFD neurons with fewer villi were also unable to orient to magnetic fields. Larvae of every stage however retained the ability to orient to thermal gradients. To our knowledge, this is the first behavioral separation of magnetic and thermal orientation in C. elegans. We conclude that magnetic orientation relies on the function of both cilia and villi in the AFD neurons. The role of villi in multiple sensory transduction pathways involved in the sensory transduction of vectorial stimuli further supports the likely role of the villi of the AFD neurons as the site for magnetic field transduction. The genetic and behavioral tractability of C. elegans make it a promising system for uncovering potentially conserved molecular mechanisms by which animals across taxa detect and orient to magnetic fields.

Long-term deficits of the paretic limb follow post-stroke compensatory limb use in C57BL/6 mice.

Stroke is a leading cause of long-term disability that most often results in impairment of a single limb, contralateral to the injury (paretic limb). While stroke survivors often receive some type of rehabilitative training, chronic deficits persist. It has been suggested that compensatory use of the nonparetic limb immediately after injury may underlie these long-term consequences. The current study investigated the behavioral effects of early compensatory limb use on behavioral outcome of the paretic limb in a mouse model of stroke. Mice received unilateral stroke after acquiring skilled motor performance on a reaching task. Following injury, mice received either delayed rehabilitation of the paretic limb or compensatory limb training prior to delayed rehabilitative training. After 28 days of focused rehabilitative training of the paretic limb, mice that had previously received compensatory limb training exhibited performance that was similar to their initial deficit after stroke while mice that received delayed rehabilitative training improved to pre-operative performance levels. Our results indicate that even with extensive focused training of the paretic limb, early compensatory limb use has a lasting impact on the behavioral flexibility and ultimate functional outcome of the paretic limb.