Integrin α11β1 is a receptor for collagen XIII

Collagen XIII is a conserved transmembrane collagen mainly expressed in mesenchymal tissues. Previously, we have shown that collagen XIII modulates tissue development and homeostasis. Integrins are a family of receptors that mediate signals from the environment into the cells and vice versa. Integrin α11β1 is a collagen receptor known to recognize the GFOGER (O=hydroxyproline) sequence in collagens. Interestingly, collagen XIII and integrin α11β1 both have a role in the regulation of bone homeostasis. To study whether α11β1 is a receptor for collagen XIII, we utilized C2C12 cells transfected to express α11β1 as their only collagen receptor. The interaction between collagen XIII and integrin α11β1 was also confirmed by surface plasmon resonance and pull-down assays. We discovered that integrin α11β1 mediates cell adhesion to two collagenous motifs, namely GPKGER and GF(S)QGEK, that were shown to act as the recognition sites for the integrin α11-I domain. Furthermore, we studied the in vivo significance of the α11β1-collagen XIII interaction by crossbreeding α11 null mice (Itga11−/−) with mice overexpressing Col13a1 (Col13a1oe). When we evaluated the bone morphology by microcomputed tomography, Col13a1oe mice had a drastic bone overgrowth followed by severe osteoporosis, whereas the double mutant mouse line showed a much milder bone phenotype. To conclude, our data identifies integrin α11β1 as a new collagen XIII receptor and demonstrates that this ligand-receptor pair has a role in the maintenance of bone homeostasis.

Loss of BubR1 Acetylation instigates Replication Stress leading to Complex Chromosomal Rearrangement in tumors

Chromosome number and structure instability is the hallmark of cancer. Equal chromosome segregation is guaranteed by the spindle assembly checkpoint (SAC), thus defective SAC leads to chromosome instability. However, aneuploidy alone is not oncogenic, and whether compromised SAC is associated with structure instability remains elusive. BubR1 is a core component of SAC, which is acetylated at lysine 250 in mitosis. Previously, we showed that deficiency of BubR1 acetylation in mice (K243R/+) leads to spontaneous tumorigenesis via chromosome mis-segregation. Here, we asked whether loss of BubR1 acetylation is associated with chromosome structure instability by examiningK243R/+mice intercrossed top53-deficient mice. Genome-wide sequencing and spectral karyotyping of the double mutant mouse tumors revealed that BubR1 acetylation deficiency leads to complex chromosome rearrangements, including Robertsonian-like whole-arm translocations and premature sister-chromatid separations (PMSCS). In primary MEFs, replication stress was markedly increased in telomeres and centromeres, suggesting that the replication stress underlies the significant increase of DNA damage and subsequent chromosome rearrangements. Furthermore, defects in BubR1 acetylation at K250 were detected in human cancers as well. Collectively, we propose that chromosome mis-segregation by the loss of BubR1 acetylation causes chromosome structure instability, leading to massive chromosome rearrangements through the induction of replication stress.

Robo1 and 2 repellent receptors cooperate to guide facial neuron cell migration and axon projections in the embryonic mouse hindbrain

Background: The facial nerve is necessary for our ability to eat, speak, and make facial expressions. Both the axons and cell bodies of the facial nerve undergo a complex embryonic migration pattern involving migration of the cell bodies caudally and tangentially through rhombomeres, and simultaneously the axons projecting to exit the hindbrain to form the facial nerve. Results: Our goal in this study was to test the functions of the chemorepulsive receptors Robo1 and Robo2 in facial neuron and axon migration by analyzing genetically marked motor neurons in double mutant mouse embryos through the migration time course, E10.0-E13.5. In Robo1/2 double mutants, axon and cell body migration errors were more severe than in single mutants. Most axons did not make it to their motor exit point, and instead projected into and longitudinally within the floor plate. Surprisingly, some facial neurons had bifurcated axons that either exited or projected into the floor plate. At the same time, a subset of mutant facial cell bodies failed to migrate caudally, and instead shifted into the floor plate. Conclusions: Robo1 and Robo2 have redundant functions to guide multiple aspects of the complex cell migration of the facial nucleus, as well as regulating axon trajectories and suppressing formation of ectopic axons.

Genetic and Diet-Induced Obesity Increased Intestinal Tumorigenesis in the Double Mutant Mouse Model Multiple Intestinal Neoplasia X Obese via Disturbed Glucose Regulation and Inflammation

We have studied how spontaneous or carcinogen-induced intestinal tumorigenesis was affected by genetic or diet-induced obesity in C57BL/6J-ApcMin/+X C57BL/6J-Lepob/+mice. Obesity was induced by theobese(ob) mutation in thelepgene coding for the hormone leptin, or by a 45% fat diet. The effects of obesity were examined on spontaneous intestinal tumors caused by themultiple intestinal neoplasia(Min) mutation in theadenomatous polyposis coli(Apc) gene and on tumors induced by the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). F1 ob/ob (homozygous mutated) mice had increased body weight (bw) and number of spontaneous and PhIP-induced small intestinal tumors (inApcMin/+mice), versus ob/wt (heterozygous mutated) and wt/wt mice (homozygous wild-type). A 45% fat diet exacerbated bw and spontaneous tumor numbers versus 10% fat, but not PhIP-induced tumors. Except for bw, ob/wt and wt/wt were not significantly different. The obesity caused hyperglucosemia and insulinemia in ob/ob mice. A 45% fat diet further increased glucose, but not insulin. Inflammation was seen as increased TNFαlevels in ob/ob mice. Thus the results implicate disturbed glucose regulation and inflammation as mechanisms involved in the association between obesity and intestinal tumorigenesis. Ob/ob mice had shorter lifespan than ob/wt and wt/wt mice.

Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire

Key Points NKG2D, but not NKp46, has a modest, NK cell intrinsic influence on shaping the NK cell receptor repertoire. NKG2D deficiency does not alter the NK cell response to MCMV infection.