Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice

Nuclear factor I (NFI) genes are expressed in multiple organs throughout development (Chaudhry et al., 1997; for review, see Gronostajski, 2000). All four NFI genes are expressed in embryonic mouse brain, with Nfia, Nfib, and Nfix being expressed highly in developing cortex (Chaudhry et al., 1997). Disruption of the Nfia gene causes agenesis of the corpus callosum (ACC), hydrocephalus, and reduced GFAP expression (das Neves et al., 1999). Three midline structures, the glial wedge, glia within the indusium griseum, and the glial sling are involved in development of the corpus callosum (Silver et al., 1982; Silver and Ogawa, 1983; Shu and Richards, 2001). Because Nfia(-/-) mice show glial abnormalities and ACC, we asked whether defects in midline glial structures occur in Nfia(-/-) mice. NFI-A protein is expressed in all three midline populations. In Nfia(-/-) mice sling cells are generated but migrate abnormally into the septum and do not form a sling. Glia within the indusium griseum and the glial wedge are greatly reduced or absent and consequently Slit2 expression is also reduced. Although callosal axons approach the midline, they fail to cross and extend aberrantly into the septum. The hippocampal commissure is absent or reduced, whereas the ipsilaterally projecting perforating axons (Hankin and Silver, 1988; Shu et al., 2001) appear relatively normal. These results support an essential role for midline glia in callosum development and a role for Nfia in the formation of midline glial structures

Netrin-DCC signaling regulates corpus callosum formation through attraction of pioneering axons and by modulating Slit2-mediated repulsion

The left and right sides of the nervous system communicate via commissural axons that cross the midline during development using evolutionarily conserved molecules. These guidance cues have been particularly well studied in the mammalian spinal cord, but it remains unclear whether these guidance mechanisms for commissural axons are similar in the developing forebrain, in particular for the corpus callosum, the largest and most important commissure for cortical function. Here, we show that Netrin1 initially attracts callosal pioneering axons derived from the cingulate cortex, but surprisingly is not attractive for the neocortical callosal axons that make up the bulk of the projection. Instead, we show that Netrin-deleted in colorectal cancer signaling acts in a fundamentally different manner, to prevent the Slit2-mediated repulsion of precrossing axons thereby allowing them to approach and cross the midline. These results provide the first evidence for how callosal axons integrate multiple guidance cues to navigate the midline

Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice

Cyclin-dependent kinase 5 (CDK5) regulates important neuronal functions via p35. p35 undergoes cleavage in response to neuronal activity and neurotoxic conditions to release its subunit p25. Although p25 has been implicated in various neurodegenerative diseases, the mechanisms by which p25 mediates neurodegenerative impairment have not been fully elucidated. We aimed to determine the role of p25-mediated neurodegeneration on neurogenesis in an inducible transgenic mouse line overexpressing p25 (p25 TG) in the forebrain. Adult neuronal progenitor cells (NPCs) were labeled with BrdU in vivo, which were significantly increased in numbers in the subventricular zone, the hippocampus, and the cortex of p25 TG mice. Consistently, more mitotic cells were observed in p25 TG mice than in controls, even in the cortex and the CA1, which are not neurogenic regions. BrdU-positive cells were negative for GFAP or γ-H2AX, suggesting that they are not astrocytes or dying cells. Neurospheres derived from the dentate gyrus and the cortex were significantly increased in p25 TG mice and can be differentiated into astrocytes and neurons. However, p25 TG decreased the long-term survival of proliferating NPCs and severely impaired adult neurogenesis. A Transwell co-culture system was used to assess the influence of p25-expressing primary neurons on adult NPCs. Co-culture with p25-expressing neurons downregulated Ki67 expression and upregulated cleaved caspase-3, indicating that the paracrine signaling in cell-cell communication is essential for NPC survival and proliferation. Moreover, increased CDK5 activity impairs Wnt activation. This study demonstrates that hyperactivation of p25 may temporarily enhance NPC proliferation, but impair their long-term survival.Brain & Behavior Research Foundation (NARSAD Young Investigator Award)American Heart Association (American Heart Scientist Development Award)National Institutes of Health (U.S.) (NIH R01AG046174)National Natural Science Foundation (China) (Grant No. 81560205)National University of Defense Technology (China) (Research Foundation (JC 14-02-01))Neurodegeneration ConsortiumGlenn Foundation for Medical Researc

A programmable nonlinear acoustic metamaterial

Acoustic metamaterials with specifically designed lattices can manipulate acoustic/elastic waves in unprecedented ways. Whereas there are many studies that focus on passive linear lattice, with non-reconfigurable structures. In this letter, we present the design, theory and experimental demonstration of an active nonlinear acoustic metamaterial, the dynamic properties of which can be modified instantaneously with reversibility. By incorporating active and nonlinear elements in a single unit cell, a real-time tunability and switchability of the band gap is achieved. In addition, we demonstrate a dynamic “editing” capability for shaping transmission spectra, which can be used to create the desired band gap and resonance. This feature is impossible to achieve in passive metamaterials. These advantages demonstrate the versatility of the proposed device, paving the way toward smart acoustic devices, such as logic elements, diode and transistor

Doublecortin-like Kinase Controls Neurogenesis by Regulating Mitotic Spindles and M Phase Progression

SummaryThe mechanisms controlling neurogenesis during brain development remain relatively unknown. Through a differential protein screen with developmental versus mature neural tissues, we identified a group of developmentally enriched microtubule-associated proteins (MAPs) including doublecortin-like kinase (DCLK), a protein that shares high homology with doublecortin (DCX). DCLK, but not DCX, is highly expressed in regions of active neurogenesis in the neocortex and cerebellum. Through a dynein-dependent mechanism, DCLK regulates the formation of bipolar mitotic spindles and the proper transition from prometaphase to metaphase during mitosis. In cultured cortical neural progenitors, DCLK RNAi Lentivirus disrupts the structure of mitotic spindles and the progression of M phase, causing an increase of cell-cycle exit index and an ectopic commitment to a neuronal fate. Furthermore, both DCLK gain and loss of function in vivo specifically promote a neuronal identity in neural progenitors. These data provide evidence that DCLK controls mitotic division by regulating spindle formation and also determines the fate of neural progenitors during cortical neurogenesis

Bilateral impairments of quadriceps neuromuscular function occur early after anterior cruciate ligament injury

The study aimed to investigate the impairments in quadriceps neuromuscular function, including strength, rate of torque development (RTD) and activation failure (QAF) early after an ACL injury. A cross-sectional study was conducted. Thirty physically active patients with a primary ACL injury within three months, aged 18 to 40 years old, and who were scheduled for ACL reconstruction were included. Thirty matched healthy controls were also recruited. All the outcomes were measured on an isokinetic dynamometer with knee flexion at 45°. Quadriceps strength was measured by maximal voluntary isometric contractions (MVIC). Early (RTD0-50) and late (RTD100-200) phases of RTD were retrieved from the MVIC test from 0 to 50 ms and 100–200 ms, respectively. QAF was quantified by the central activation ratio (CAR) measured by superimposed burst technique. The results of Mann–Whitney U test showed that compared with the healthy limbs, the injured limbs of the ACL group showed lower quadriceps strength (P 0-50 (P 100-200 (P 0-50 (P = 0.006) as well as greater QAF (P = 0.010). To conclude, bilateral quadriceps suffered from neuromuscular impairments early after an ACL injury.</p

The spatial and temporal expression patterns of netrin receptors, DCC and neogenin, in the developing mouse retina

Recently it has been demonstrated that the guidance of retinal ganglion cell (rgc) axons through the optic disc is dependent on the DCC/netrin-1 axonal guidance system. To gain further insight into the function of the netrin receptors, DCC and Neogenin, in retinal development we ha ire studied the expression patterns of these receptors in the embryonic mouse retina. Neogenin mRNA was restricted tb a single neural cell type, the rgc. However, strong Neogenin mRNA expression was observed in the extending fiber cells of the developing lens suggesting a role for Neogenin in the migration events shaping the early lens, Our studies demonstrated that DCC mRNA was expressed at high levels in chains of closely opposed neurons as they migrated towards the emerging mantle layer in the early retina (E12.5-E13.5) suggesting a role for DCC in the migration of neurons out of the ventricular zone. DCC protein expression was high on rgc axons as they actively navigated through the optic disc into the optic nerve. At birth, when the majority of rgc axons had projected through the optic disc, DCC protein was no longer detectable on the distal axonal segments within the optic nerve despite significant DCC protein expression on the proximal axonal membranes in the nerve fiber layer. These observations suggest that a localized down-regulation of DCC protein occurs on projecting axonal membranes once the DCC guidance function is no longer required. We also demonstrated that DCC mRNA and protein were expressed by amacrine cells and Muller glial cells while DCC mRNA was detected in horizontal cells. Taken together, these expression patterns suggest a role far DCC in axon outgrowth and/or pathfinding for a variety of retinal neurons and in the migration of newly born neurons within the developing retina