Biology subjects

Howard, E. M.

Publications and source records attributed to Howard, E. M..

3 recordsLinked to original sources

bioRxiv2026

Myosin 5A mediates membrane-associated periodic skeleton reassembly during axon regeneration in response to ROCK-2 inhibition

The membrane-associated periodic skeleton (MPS) is a submembrane lattice composed of actin rings and spectrin tetramers that repeats every 190 nm along axons and maintains mechanical stability. Loss of the MPS precedes axon fragmentation during degeneration, but during axon regrowth after injury the extent and timing of MPS reformation are not clear. We used stimulated emission depletion (STED) microscopy to track {beta}II-spectrin periodicity in regenerating axons from mouse cortical neurons, human iPSC-derived cortical neurons, and human iPSC-derived motor neurons following mechanical axotomy. Regrowing axons initially lack periodic {beta}II-spectrin organization, particularly near the growth cone. Over 8 to 15 days, periodicity is partially restored in intermediate axonal regions, while distal segments remain disorganized. We found that reducing Rho kinase ROCK-2 activity either pharmacologically or by CRISPRi promotes axon regrowth and accelerates MPS recovery rate five-fold, reaching near-normal levels by 3 days post-injury. To identify the key effectors, we performed co-immunoprecipitation mass spectrometry of the {beta}II-spectrin complex under injury and ROCK-2-inhibited conditions. Myosin 5A (MYO5A) association with spectrin rose sharply upon injury and further increased when ROCK-2 was absent. Functional experiments positioned MYO5A downstream of ROCK-2. Knocking down MYO5A abolished the enhanced regrowth of ROCK-2-deficient neurons, while overexpressing MYO5A increased regrowth in wild-type neurons. Depleting MYO5A also partially disrupted {beta}II-spectrin periodicity in healthy, uninjured axons, indicating a requirement for MYO5A in MPS maintenance under physiological conditions. STED imaging demonstrated that ROCK-2 is arranged periodically along the axon at 190 nm intervals, suggesting it regulates the local lattice. These findings define a ROCK-2/MYO5A pathway linking a targetable kinase to nanoscale cytoskeletal repair and axon regeneration.

neuroscience↗

bioRxiv2025

Axon Regeneration and Functional Recovery after Spinal Cord Injury is Enhanced by Allele-Specific ApoE Neuronal Action through LRP8

Adult CNS trauma frequently causes neuronal disconnection and persistent deficits due to failed axon regeneration. While model system screening has identified multiple candidate neural repair pathways, ApoE-LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by APOE variants. ApoE2-expressing mice show reparative corticospinal and raphespinal axon growth with greater motor function than controls after spinal cord injury. Distinct from ApoE in other settings, there is no change in inflammation or scarring. After axotomy, ApoE exerts allele-specific effects on LRP8 localization and signaling in cortical neurons. APOE alleles regulate synaptic organization gene expression by cortical neurons after injury, with little effect on glial gene expression. AAV-mediated overexpression of ApoE2 in mice after spinal trauma increases locomotor recovery and reparative axon growth. Thus, ApoE-LRP8 signaling for axon regrowth following CNS trauma provides a potential therapeutic intervention site.

neuroscience↗

bioRxiv2020

Biogeochemical variability in the California Current System

The biological productivity and diversity of the California Current System (CCS) is at the leading edge of major emerging climate trends, including hypoxia and acidification. We present results from a hindcast simulation (reanalysis) of an eddy-resolving oceanic physical-biogeochemical model of the CCS, to characterize its mean state and its patterns and drivers of variability in marine biogeochemical and ecosystem processes from 1995-2010. This is a companion paper to a physical analysis in Renault et al. (2021). The model reproduces long-term mean distributions of key ecosystem metrics, including surface nutrients and productivity and subsurface O2 and carbonate undersaturation. The spatial patterns of Net Primary Productivity (NPP) are broadly consistent with measured and remotely sensed rates, and they reflect a predominant limitation by nitrogen, with seasonal and episodic limitation by Fe nearshore in the central CCS, and in the open ocean northern CCS. The vertical distribution of NPP is governed by the trade-off between nutrient and light limitation, a balance that reproduces and explains the observed spatial variations in the depth of the deep Chl maximum. The seasonal to interannual variability of biogeochemical properties and rates is also well captured by model simulations. Because of the prevailing nutrient limitation, fluctuations in the depth of the pycnocline and associated nutricline are the leading single factor explaining interannual variability in the interior biogeochemical state, and the relationships between density and biogeochemical rates and tracers are consistent between model and observations. The magnitude and relationship between density structure and biogeochemical processes is illustrated by the 1997-98 El Nino event, which faithfully reproduces the single largest deviation from the mean state in the simulated period. A slower decadal shoaling of the pycnocline also accounts for the concomitant trends in hypoxic and corrosive conditions on the shelf. The resulting variability is key to understanding the vulnerability of marine species to oceanic change, and to the detection of such changes, soon projected to exceed the range of conditions in the past century.

ecology↗