Ndel1 alters its conformation by sequestering cAMP-specific phosphodiesterase-4D3 (PDE4D3) in a manner that is dynamically regulated through Protein Kinase A (PKA)

The involvement of the Nuclear distribution element-like (Ndel1; Nudel) protein in the recruitment of the dynein complex is critical for neurodevelopment and potentially important for neuronal disease states. The PDE4 family of phosphodiesterases specifically degrades cAMP, an important second messenger implicated in learning and memory functions. Here we show for the first time that Ndel1 can interact directly with PDE4 family members and that the interaction of Ndel1 with the PDE4D3 isoform is uniquely disrupted by elevation of intracellular cAMP levels. While all long PDE4 isoforms are subject to stimulatory PKA phosphorylation within their conserved regulatory UCR1 domain, specificity for release of PDE4D3 is conferred due to the PKA-dependent phosphorylation of Ser13 within the isoform-specific, unique amino-terminal domain of PDE4D3. Scanning peptide array analyses identify a common region on Ndel1 for PDE4 binding and an additional region that is unique to PDE4D3. The common site lies within the stutter region that links the second coiled-coil region to the unstable third coiled-coil regions of Ndel1. The additional binding region unique to PDE4D3 penetrates into the start of the third coiled-coil region that can undergo tail-to-tail interactions between Ndel1 dimers to form a 4 helix bundle. We demonstrate Ndel1 self-interaction in living cells using a BRET approach with luciferase- and GFP-tagged forms of Ndel1. BRET assessed Ndel1–Ndel1 self-interaction is amplified through the binding of PDE4 isoforms. For PDE4D3 this effect is ablated upon elevation of intracellular cAMP due to PKA-mediated phosphorylation at Ser13, while the potentiating effects of PDE4B1 and PDE4D5 are resistant to cAMP elevation. PDE4D long isoforms and Ndel1 show a similar sub-cellular distribution in hippocampus and cortex and locate to post-synaptic densities. We show that Ndel1 sequesters EPAC, but not PKA, in order to form a cAMP signalling complex. We propose that a key function of the Ndel1 signalling scaffold is to signal through cAMP by sequestering EPAC, whose activity may thus be specifically regulated by sequestered PDE4 that also stabilizes Ndel1–Ndel1 self-interaction. In the case of PDE4D3, its association with Ndel1 is dynamically regulated by PKA input through its ability to phosphorylate Ser13 in the unique N-terminal region of this isoform, triggering the specific release of PDE4D3 from Ndel1 when cAMP levels are elevated. We propose that Ser13 may act as a redistribution trigger in PDE4D3, allowing it to dynamically re-shape cAMP gradients in distinct intracellular locales upon its phosphorylation by PKA.     

Range‐wide multilocus phylogeography of the red fox reveals ancient continental divergence,minimal genomic exchange and distinct demographic histories

Widely distributed taxa provide an opportunity to compare biogeographic responses to climatic fluctuations on multiple continents and to investigate speciation. We conducted the most geographically and genomically comprehensive study to date of the red fox (Vulpes vulpes), the world's most widely distributed wild terrestrial carnivore. Analyses of 697 bp of mitochondrial sequence in ~1000 individuals suggested an ancient Middle Eastern origin for all extant red foxes and a 400 kya (SD = 139 kya) origin of the primary North American (Nearctic) clade. Demographic analyses indicated a major expansion in Eurasia during the last glaciation (~50 kya), coinciding with a previously described secondary transfer of a single matriline (Holarctic) to North America. In contrast, North American matrilines (including the transferred portion of Holarctic clade) exhibited no signatures of expansion until the end of the Pleistocene (~12 kya). Analyses of 11 autosomal loci from a subset of foxes supported the colonization time frame suggested by mtDNA (and the fossil record) but, in contrast, reflected no detectable secondary transfer, resulting in the most fundamental genomic division of red foxes at the Bering Strait. Endemic continental Y‐chromosome clades further supported this pattern. Thus, intercontinental genomic exchange was overall very limited, consistent with long‐term reproductive isolation since the initial colonization of North America. Based on continental divergence times in other carnivoran species pairs, our findings support a model of peripatric speciation and are consistent with the previous classification of the North American red fox as a distinct species, V. fulva.     

Do no-take reserves benefit Florida’s corals? 14 years of change and stasis in the Florida Keys National Marine Sanctuary

With coral populations in decline globally, it is critical that we tease apart the relative impacts of ecological and physical perturbations on reef ecosystems to determine the most appropriate management actions. This study compared the trajectories of benthic assemblages from 1998 to 2011 in three no-take reserves and three sites open to fishing, at 7–9 and 15–18 m depth in the Florida Keys. We evaluated temporal changes in the benthic assemblage to infer whether fisheries bans in no-take reserves could have cascading effects on the benthos in this region. Coral cover declined significantly over time at our sites and that trend was driven almost exclusively by decline of the Orbicella (formerly Montastraea) annularis species complex. Other coral taxa showed remarkable stasis and resistance to a variety of environmental perturbations. Protection status did not influence coral or macroalgal cover. The dynamics of corals and macroalgae in the 15 years since the reserves were established in 1997 suggest that although the reserves protected fish, they were of no perceptible benefit to Florida’s corals.     

Linear skin markings in common bottlenose dolphins (Tursiops truncatus) from the Indian River Lagoon,Florida

A previously undescribed skin abnormality, referred to as “linear skin markings” (LSM), has been identified in free-ranging common bottlenose dolphins (Tursiops truncatus) in the Indian River Lagoon, Florida (IRL). The lesions were identified during photo-identification surveys conducted from 2002 and 2015. LSM presented as distinct, parallel lines running dorso-ventrally on the torso and varied in length and width. The goals of this study were to determine (1) prevalence of the condition in IRL dolphins, (2) age and sex distribution of affected animals, (3) spatial and temporal distribution patterns, (4) duration of the condition, and (5) development of hypotheses regarding the etiology of the condition. Among 1,357 individual dolphins identified during the study period, 96 (7.0%) showed evidence of LSM. Nearly all (98.8%) cases with an established home range occurred in the northern and central regions of the IRL. The majority of cases of known sex were female (85%), of which 100% had given birth to one or more calves. The mean age of animals with LSM when first observed was 7.3 with a range of 1–20 years. The maximum observed duration of LSM was 15 years. Once observed, the condition persisted indefinitely. The etiology of LSM has not been established.     

Proteolytic and cellular death mechanisms in ovulatory ovarian rupture

Collagen breakdown and cellular death (apoptosis and inflammatory necrosis) within the apex of preovulatory ovine follicles are hallmarks of impending ovarian rupture. An integrative mechanism is presented whereby gonadotropic stimulation of urokinase-type plasminogen activator secretion by ovarian surface epithelial cells bordering the preovulatory follicle elicits a localized increase in tissue plasmin, which activates latent collagenases and secretion of tumor necrosis factor-alpha (TNF-alpha) from thecal endothelium. TNF-alpha potentiates collagenolysis (via matrix metalloproteinase gene expression) and (at elevated concentrations) mediates epithelial/vascular dissolution. Incidental damage to DNA of ovarian surface epithelial cells circumjacent to the ruptured follicle is a putative etiological factor in ovarian cancer.