ALBERT

Description: The cadherin–catenin complex (CCC) mediates cell–cell adhesion in bilaterian animals by linking extracellular cadherin-based adhesions to the actin cytoskeleton. However, it is unknown whether the basic organization of the complex is conserved across all metazoans. We tested whether protein interactions and actin-binding properties of the CCC are conserved in a nonbilaterian animal, the sea anemone Nematostella vectensis . We demonstrated that N. vectensis has a complete repertoire of cadherin–catenin proteins, including two classical cadherins, one α-catenin, and one β-catenin. Using size-exclusion chromatography and multi-angle light scattering, we showed that α-catenin and β-catenin formed a heterodimer that bound N. vectensis Cadherin-1 and -2. Nematostella vectensis α-catenin bound F-actin with equivalent affinity as either a monomer or an α/β-catenin heterodimer, and its affinity for F-actin was, in part, regulated by a novel insert between the N- and C-terminal domains. Nematostella vectensis α-catenin inhibited Arp2/3 complex-mediated nucleation of actin filaments, a regulatory property previously thought to be unique to mammalian αE-catenin. Thus, despite significant differences in sequence, the key interactions of the CCC are conserved between bilaterians and cnidarians, indicating that the core function of the CCC as a link between cell adhesions and the actin cytoskeleton is ancestral in the eumetazoans.

Description: Charcot–Marie–Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

Description: Mafic to ultramafic intrusions of the Qullinaaraaluk suite (Q-suite) were emplaced into the Ungava craton of the Northeastern Superior Province during an episode of intense igneous activity and crustal reworking from c. 2·74 to 2·70 Ga. Orthopyroxene-rich Q-suite intrusions from the Hudson Bay Terrane and southwestern Rivière Arnaud Terrane, and orthopyroxene-poor Q-suite intrusions from the north–central Rivière Arnaud Terrane indicate the existence of at least two Q-suite magma types: a subalkaline magma parental to the orthopyroxene-rich intrusions and a transitional magma parental to the orthopyroxene-poor intrusions. Both types of intrusions are characterized by light rare earth element (LREE)-enriched, high field strength element (HFSE)-depleted trace element profiles that reflect, in large part, contamination by the tonalite–trondhjemite–granodiorite-dominated crust. Near-chondritic to strongly sub-chondritic initial Nd (2·72 Ga) values (+2 to –10) of the Q-suite intrusions reflect the combined effects of both the amount of crustal contamination and the age-dependent isotopic composition of the contaminant. The inferred trace element profiles of the uncontaminated Q-suite magmas were probably flat to LREE-depleted. The transitional magmas that produced the least evolved dunitic cumulates of the Q-suite were ferropicrites (MgO ~14 wt %, FeO TOT ~17 wt %). In contrast, the magmas parental to the primitive Q-suite harzburgites were Fe-rich, high-Mg basalts (MgO ~11 wt %; FeO ~14 wt %). The high Fe contents of the Q-suite magmas are incompatible with derivation from a pyrolitic mantle [Mg-number ~0·90, Mg/(Mg + Fe TOT )] and require sources significantly enriched in iron (Mg-number ≤0·79). Both magma types are also characterized by relatively low Ni contents suggesting derivation from source regions depleted in Ni relative to pyrolitic mantle peridotite. Differences in the major element compositions of the subalkaline and transitional parental magmas may reflect compositional diversity among the Fe-rich mantle sources. Comparisons with melting experiments on compositions analogous to the Martian mantle suggest that the Q-suite magmas may rather be generated by different degrees of melting of a common source with an Fe content slightly lower than that of the Homestead L5 ordinary chondrite (Mg-number = 0·77). The Fe-rich picritic to high-Mg basaltic magmas last equilibrated with garnet-free harzburgitic to lherzolitic residues at upper mantle pressures (≤5 GPa). The craton-wide occurrence of c. 2·72–2·70 Ga Q-suite mafic to ultramafic plutons suggests that underplating by Fe-rich mantle melts may have had a key role in the c. 2·74–2·70 Ga cratonization of the Northeastern Superior Province.

Description: Mid-ocean ridge basalts (MORB) from the Arctic Ocean have been significantly less studied than those from other oceans. The Arctic ridges (Gakkel Ridge and Lena Trough) are ultraslow-spreading ridges with low melt productivity and are thus the best locations to investigate mantle heterogeneity. We report the major and trace element and Sr–Nd–Pb–Hf isotope compositions of basalts generated along the Lena Trough and the westernmost part of the Gakkel Ridge in the Arctic Ocean. Basalts from the northern Lena Trough and westernmost Gakkel Ridge (NLT–WGR) have compositions close to normal MORB. The geochemical composition of the NLT–WGR lavas confirms a binary mixing model involving melts from a depleted MORB mantle source and a Spitsbergen amphibole-bearing subcontinental lithospheric mantle (SCLM) source. In contrast, in the central part of the Lena Trough (CLT), the basalts are alkalic with relatively high Mg-number (60–65), high SiO 2 (51·0–51·6 wt %), Al 2 O 3 (18·1–18·4 wt %), Na 2 O (4·0–4·2 wt %), K 2 O (1·0–1·6 wt %), K 2 O/TiO 2 (0·6–0·9) and (La/Sm) PM (1·4–1·8), and low FeO (6·5–6·8 wt %) contents. These basalts display isotope variations with 87 Sr/ 86 Sr ranging from 0·70361 to 0·70390, 143 Nd/ 144 Nd from 0·51283 to 0·51290 ( Nd + 3·7 to +5·2), 176 Hf/ 177 Hf from 0·28313 to 0·28322 ( Hf + 11·6 to +14·9) and 206 Pb/ 204 Pb from 17·752 to 17·884, 207 Pb/ 204 Pb from 15·410 to 15·423 and 208 Pb/ 204 Pb from 37·544 to 37·670. These isotope compositions clearly distinguish the CLT lavas from those generated along the Gakkel Ridge. For the CLT lavas, involvement of a phlogopite- or amphibole- and (possibly garnet)-bearing SCLM source component is proposed. Owing to SCLM contamination along the entire length of the Lena Trough, we classify the Lena Trough as an ocean–continent transition boundary. Magmatism similar to that observed in the Lena Trough would be expected to occur wherever ocean spreading initiates.

Description: The anatomy and development of the tails at the posterior part of the mantle were studied in several groups of Recent and extinct coleoid cephalopods; substantial differences in their formation were revealed. Males of the Recent loliginid squid Alloteuthis spp. form their tail by increased growth of the anterior part of the gladius with simultaneous growth of the posterior mantle. As a result, the gladius rolls longitudinally in the tail forming a pseudoconus. The attenuated tail in males of the squid Lycoteuthis springeri (Lycoteuthidae) is supported from inside by the special rod-like apical vacuolated cartilage. Adults of both sexes of recent Onykia robsoni and O. robusta form a carrot-shaped flexible chitinous rostrum supporting the attenuated tail. Adults of several Jurassic belemnites formed an elongated epirostrum posterior to their orthorostrum; the structures differed in growth and microstructure. Counts of growth microincrements within the orthorostrum and epirostrum were used to date their formation and estimate the age of belemnites. The development of the long rigid tail and the corresponding shift of the fin to the middle part of the mantle streamline the body and possibly facilitate the animal's movement in the water by gliding. The analogous tail formation in several independent groups points to its adaptive nature for the development of a more mobile adult phase in species of coleoid cephalopods.

Description: Although biallelic mutations in non-collagen genes account for 〈10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10 , which encodes the 65 kDa prolyl cis–trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10 , PLOD2 and SERPINH1 , that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

Description: Eukaryotic ribosome biogenesis requires the concerted action of numerous ribosome assembly factors, for most of which structural and functional information is currently lacking. Nob1, which can be identified in eukaryotes and archaea, is required for the final maturation of the small subunit ribosomal RNA in yeast by catalyzing cleavage at site D after export of the preribosomal subunit into the cytoplasm. Here, we show that this also holds true for Nob1 from the archaeon Pyrococcus horikoshii , which efficiently cleaves RNA-substrates containing the D-site of the preribosomal RNA in a manganese-dependent manner. The structure of PhNob1 solved by nuclear magnetic resonance spectroscopy revealed a PIN domain common with many nucleases and a zinc ribbon domain, which are structurally connected by a flexible linker. We show that amino acid residues required for substrate binding reside in the PIN domain whereas the zinc ribbon domain alone is sufficient to bind helix 40 of the small subunit rRNA. This suggests that the zinc ribbon domain acts as an anchor point for the protein on the nascent subunit positioning it in the proximity of the cleavage site.

Description: Osteogenesis imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations in the type I procollagen genes, but mutations in a growing number of genes have been identified that produce autosomal recessive forms of the disease. Among these include mutations in the genes SERPINH1 and FKBP10 , which encode the type I procollagen chaperones HSP47 and FKBP65, respectively, and predominantly produce a moderately severe form of OI. Little is known about the biochemical consequences of the mutations and how they produce OI. We have identified a new OI mutation in SERPINH1 that results in destabilization and mislocalization of HSP47 and secondarily has similar effects on FKBP65. We found evidence that HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen and that FKBP65 and HSP47 but fail to properly interact in mutant HSP47 cells. These results thus reveal a common cellular pathway in cases of OI caused by HSP47 and FKBP65 deficiency.

Description: Osteogenesis imperfecta (OI) is an inherited brittle bone disorder characterized by bone fragility and low bone mass. Loss of function mutations in FK506-binding protein 10 ( FKBP10 ), encoding the FKBP65 protein, result in recessive OI and Bruck syndrome, of which the latter is additionally characterized by joint contractures. FKBP65 is thought to act as a collagen chaperone, but it is unknown how loss of FKBP65 affects collagen synthesis and extracellular matrix formation. We evaluated the developmental and postnatal expression of Fkbp10 and analyzed the consequences of its generalized loss of function. Fkbp10 is expressed at low levels in E13.5 mouse embryos, particularly in skeletal tissues, and steadily increases through E17.5 with expression in not only skeletal tissues, but also in visceral tissues. Postnatally, expression is limited to developing bone and ligaments. In contrast to humans, with complete loss of function mutations, Fkbp10 –/– mice do not survive birth, and embryos present with growth delay and tissue fragility. Type I calvarial collagen isolated from these mice showed reduced stable crosslink formation at telopeptide lysines. Furthermore, Fkbp10 –/– mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated endoplasmic reticulum. These data suggest a requirement for FKBP65 function during embryonic connective tissue development in mice, but the restricted expression postnatally in bone, ligaments and tendons correlates with the bone fragility and contracture phenotype in humans.