Search bioRxiv⌕ Search

bioRxiv · 10.1101/2024.07.30.605892

MLCK/MLCP regulates mammalian axon regeneration via the redistribution of the growth cone F-actin

Abstract

Axon regrowth is a key determinant of the restoration of the biological function of the nervous system after trauma. However, mature mammalian neurons have limited capacity for axon regeneration. We have previously demonstrated that neuronal axon growth both in the central and the peripheral nervous systems is markedly enhanced when non-muscle myosin II (NMII) is inhibited with blebbistatin. The activity of NMII is primarily regulated by MLCK and MLCP via the phosphorylation and dephosphorylation of its light chain, respectively; however, the functional roles of MLCK and MLCP in mammalian axonal regeneration remain unknown. In the present study, we provide strong evidence that the inhibition of MLCK activity significantly blocks axon regeneration in mice. Conversely, the inhibition of MLCP promotes axon regrowth of both the peripheral and central nervous system. Our findings further indicate that the MLCK/MLCP regulates axon regeneration and redistributes the growth cone F-actin, and this result suggests that direct regulation of the growth cone machinery is a potential strategy to promote axon regeneration.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

None, S., Wang, W., Ma, J., Yin, Y., Ma, Y.. 2024-07-31. MLCK/MLCP regulates mammalian axon regeneration via the redistribution of the growth cone F-actin. https://doi.org/10.1101/2024.07.30.605892

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗

Genetic Variation, Iron Status, and FGF23 Signaling Converge to Regulate Renal Calcium Buffering in Sickle Cell Disease

Sickle cell disease (SCD) causes heterogeneous mineral imbalances including variable degrees of hypocalcemia. The kidney controls systemic calcium by reabsorbing calcium from the glomerular filtrate via paracellular transport and transcellular transport in the nephron tubules, yet it is unknown whether these processes are modulated by genetic or environmental factors or disrupted in SCD. Using SCD mouse models and single-cell multiomics, we identify the distal convoluted tubule (DCT) as the nephron segment most susceptible to calcium reabsorption dysfunction in SCD, mainly via reduction of calcium buffer protein calbindin 1 (CALB1). We show that CALB1 and its encoding mRNA are decreased in DCT cells in SCD, alongside decreased Klotho (KL)-dependent fibroblast growth factor (FGF) 23 signaling and intracellular calcium signaling. Dietary iron restriction reduces CALB1, KL, and calcium exporter SLC8A1 levels in SCD kidneys. Loss of CALB1 shifts DCT cells toward energy-inefficient glycolysis with the metabolite 2,3-diphosphoglycerate impairing KL-dependent FGF23 signaling to create a feed-forward loop suppressing calcium reabsorption. Analysis of gene expression and protein quantitative trait loci data from kidneys of genetically diverse mice revealed that Calb1 expression levels are highly heritable and co-regulated with Slc8a1, identifying a genetic axis that dictates differential capacities for calcium buffering and trafficking toward blood in the kidney. Together, these findings support a model in which genetic variation, dietary iron status, and FGF23 signaling converge on DCT calcium buffering to reduce renal calcium reabsorption in the SCD kidney. This points to personalized, genotype- and iron-dependent strategies for managing mineral metabolism in SCD patients.

physiology↗

Silver spoon effect: early-life environment and adult survival in a primate.

Early environmental conditions can have long-lasting effects on survival and reproductive fitness. Using a 23 year-long monitoring data set of captive mouse lemur's life history traits, we tested a relationship between maternal allocation to offspring (N = 1365) and their adulthood survival. Maternal characteristics such as age or body condition did not affect allocation to offspring whatever the litter size (1 to 3). Although birth mass depended on size and composition of the litters, mouse lemur survival was highly correlated with body mass acquired after weaning in both sexes, through potential sibling competition. Moreover, female's reproductive success correlated with this body mass and was consistently associated with increased longevity. These findings suggest the presence of a silver spoon effect under constant captive conditions. However, cumulative effects of genetic and adulthood social conditions strongly interact to affect adult survival. Deaths related to intra- or inter-sexes aggressive social interactions may outweigh effect of early environment and therefore minimize the silver-spoon effect on captive mouse lemur's survival. However, having a high body mass after weaning appeared to be a determinant factor in individual survival for mouse lemurs.

physiology↗