Normal mitochondrial respiratory function is essential for spatial remote memory in mice

<p>Abstract</p> <p>Background</p> <p>Mitochondrial DNA (mtDNA) with pathogenic mutations has been found in patients with cognitive disorders. However, little is known about whether pathogenic mtDNA mutations and the resultant mitochondrial respiration deficiencies contribute to the expression of cognitive alterations, such as impairments of learning and memory. To address this point, we used two groups of <it>trans</it>-mitochondrial mice (mito-mice) with heteroplasmy for wild-type and pathogenically deleted (Δ) mtDNA; the "low" group carried 50% or less ΔmtDNA, and the "high" group carried more than 50% ΔmtDNA.</p> <p>Results</p> <p>Both groups had normal phenotypes for not only spatial learning, but also memory at short retention delays, indicating that ΔmtDNA load did not affect learning and temporal memory. The high group, however, showed severe impairment of memory at long retention delays. In the visual cortex and dentate gyrus of these mice, we observed mitochondrial respiration deficiencies, and reduced Ca²⁺/calmodulin-dependent kinase II-α (α-CaMKII), a protein important for the establishment of spatial remote memory.</p> <p>Conclusion</p> <p>Our results indicated that normal mitochondrial respiratory function is necessary for retention and consolidation of memory trace; deficiencies in this function due to high loads of pathogenically mutated mtDNA are responsible for the preferential impairment of spatial remote memory.</p

Patched1 Haploinsufficiency Increases Adult Bone Mass and Modulates Gli3 Repressor Activity

SummaryHedgehog (Hh)-Patched1 (Ptch1) signaling plays essential roles in various developmental processes, but little is known about its role in postnatal homeostasis. Here, we demonstrate regulation of postnatal bone homeostasis by Hh-Ptch1 signaling. Ptch1-deficient (Ptch1+/−) mice and patients with nevoid basal cell carcinoma syndrome showed high bone mass in adults. In culture, Ptch1+/− cells showed accelerated osteoblast differentiation, enhanced responsiveness to the runt-related transcription factor 2 (Runx2), and reduced generation of the repressor form of Gli3 (Gli3rep). Gli3rep inhibited DNA binding by Runx2 in vitro, suggesting a mechanism that could contribute to the bone phenotypes seen in the Ptch1 heterozygotes. Moreover, systemic administration of the Hh signaling inhibitor cyclopamine decreased bone mass in adult mice. These data provide evidence that Hh-Ptch1 signaling plays a crucial role in postnatal bone homeostasis and point to Hh-Ptch1 signaling as a potential molecular target for the treatment of osteoporosis

The potentiation of Nodal signaling in the right lateral plate mesoderm inverts the left-right specification of the internal organs.

In Xenopus, multiple nodal-related genes are expressed during early embryogenesis. Among them, only Xenopus nodal related-1(Xnr-1) is expressed unilaterally in the left lateral plate mesoderm(LPM) at the late neurula-early tailbud stage. Early studies report that ectopic administration of Xnr-1 in the right hemisphere at the cleavage stage alters the left-right specification of the heart and visceral organs, or else makes a secondary axis. However, because Xnr-1 and other Xnrs function already at the blastula-gastrula stage, it is very difficult to evaluate the correct timing of the effects of excessively administered Xnr-1 from such a method. To elucidate the essential role of Xnr-1 within the left LPM, ectopic potentiation of Nodal signaling in the right lateral plate mesoderm was performed. Right-side injection of Nodal protein changed the laterality of Xnr-1 and Xenopuspitx2, but lefty, and fully (more than 90%) reversed the situs of the internal organs. Polyethyleneimine-based gene transfer of Xnr-1 mRNA in the right LPM also changed the laterality of pitx2 and fully (more than 90%) reversed the situs of the internal organs. Taken together, the potentiation of Xnr-1 signaling in the right LPM induces pitx2 in the right side and fully inverts the left-right axis of the heart and visceral organs, suggesting that the right LPM can transduce Nodal signaling, and only the absence of the Xnr-1 ligand silences the Nodal signaling in the right LPM. Normal left-right balance of Xnr-1 signaling is needed for the normal left-right specification of the internal organs

Visualization of the Semitranslucent Brain Ventricle and Its Fluid Flow Using Microinjection Technique for Albino Xenopus laevis Larvae

In vertebrates, the central nervous system (CNS) develops as a tube called the neural tube. Ependymal cells seal the inner surface of the brain ventricle, and movement of the cilia on the apical surface of the ependymal cells generates fluid flow called cerebrospinal fluid flow. The role of cerebrospinal fluid flow for the process of neurogenesis and regionalization of the CNS remains unveiled. In this study, using albino larvae of Xenopus laevis, we report a new methodology to clearly visualize the semitranslucent morphology of the brain ventricle and patterning of the fluid flow within the cavity during amphibian CNS development. Microinjection of the quantum dot (fluorescent nanocrystal) through the roof plate of the fourth ventricle rapidly and efficiently visualized the whole brain ventricle under fluorescent micrography, enabling us to trace the complicated morphology during development of the third, fourth and lateral ventricles. Microinjection of polystyrene beads (3.1μm in diameter) into the fourth ventricle also efficiently dispersed into every corner of the brain ventricle. This technique revealed that fluid flow within fourth ventricle displays dorso-ventral asymmetry. In 60% of the embryos examined, the rearward fluid flow within the third ventricle shifted to the left at the dorsal portion of the ventricle, whereas, in the other larvae, it was quite bilateral. These results suggest that fluid flow within the developing CNS is generated by a highly integrated, position-dependent metachronal wave of cilia on ependymal cell surfaces. This report is the first description of left-right asymmetric fluid flow in the brain ventricle of vertebrates, encouraging us to examine the relationships between the laterality of tadpole behavior and left-right asymmetry underlying the molecular anatomy of the developing brain