Biology subjects

Brill, M. S.

Publications and source records attributed to Brill, M. S..

8 recordsLinked to original sources

bioRxiv2026

Mitochondrial hitch-hiking of Mapt mRNA maintains Tau levels in axons

Hitch-hiking of transcripts on organelles, including mitochondria, has emerged as a common pathway to transport mRNAs into the axon to enable their local translation. However, the extent of mitochondrial mRNA association in vivo has not been established. Here we report the landscape of mitochondrial mRNA association in two nerve tissues, the retinal ganglion cell derived optic nerve and the motor neuron derived part of the sciatic nerve. This revealed astonishing tissue diversity between mitochondria associated mRNAs that can partly be explained by the lack of expression of the mitochondrially anchored RNA-binding protein SYNJ2a in motor neurons. This diversity led us to discover that also MAPT mRNA, encoding the axon-enriched microtubule associated protein Tau, is transported via the mitochondrial RNA anchoring complex SYNJ2a/SYNJ2BP into axons of glutamatergic neurons. Loss of SYNJ2BP prevents axonal localization of MAPT and miss-sorting of Tau, consequently stunting axonal growth in cultured hippocampal neurons. This connects mitochondrial transport to the maintenance of the local cytoskeleton and axonal growth in glutamatergic neurons.

neuroscience↗

bioRxiv2025

Neuronal compartmentalization results in impoverished axonal mitochondria

Mitochondria differ depending on their location within a neuron. Morphological heterogeneity between somatic, dendritic, and axonal mitochondria is well established. Emerging evidence suggests that further specialization is needed to meet the unique demands of different neuronal compartments. However, the molecular and functional diversity of mitochondria within a neuron remains poorly understood. Here, we utilized proteomics in MitoTag mice to profile somatodendritic and axonal mitochondria across four distinct neuron types, thereby generating a compendium of intracellular mitochondrial diversity. Combining proteomics, functional, and immunofluorescence analyses, we demonstrated that axonal mitochondria are not defined by the presence of unique proteins, but rather by the selective loss or preservation of specific pathways compared to their somatodendritic counterparts. This results in "impoverished" axonal mitochondria, which are characterized by diminished mtDNA expression and impaired oxidative phosphorylation yet retain other pathways, such as fatty acid metabolism. Bioinformatic analyses of multiomic data identified local translation as one mechanism underlying compartment-specific diversity. Together, these findings provide a comprehensive in vivo framework for understanding mitochondrial specialization across neuronal compartments.

neuroscience↗

bioRxiv2024

Axon-specific microtubule regulation drives asymmetric regeneration of sensory neuron axons

Sensory dorsal root ganglion (DRG) neurons have a unique pseudo-unipolar morphology in which a stem axon bifurcates into a peripheral and a central axon, with different regenerative abilities. Whereas peripheral DRG axons regenerate, central axons are unable to regrow. Central axon regeneration can however be elicited by a prior conditioning lesion to the peripheral axon. How DRG axon asymmetry is established, remains unknown. Here we developed a rodent in vitro system replicating DRG pseudo-unipolarization and asymmetric axon regeneration. Using this model, we observed that from early development, central DRG axons have a higher density of growing microtubules. This asymmetry was also present in vivo and was abolished by a conditioning lesion that decreased microtubule polymerization of central DRG axons. An axon-specific microtubule-associated protein (MAP) signature, including the severases spastin and katanin and the microtubule regulators CRMP5 and tau, was found and shown to adapt upon conditioning lesion. Supporting its significance, interfering with the DRG MAP signature either in vitro or in vivo, readily abolished central-peripheral asymmetries in microtubule dynamics and regenerative ability. In summary, our data unveil that axon-specific microtubule regulation drives asymmetric regeneration of sensory neuron axons. Impact statementSensory neurons have a stem axon that bifurcates originating two axons with different properties. This work shows that DRG axons have a specific protein signature underlying microtubule and regeneration asymmetries. It also provides an in vitro system replicating DRG biology.

neuroscience↗

bioRxiv2024

A retrograde transit filter mediated by optineurin controls mitostasis in distal axons

The mechanisms of mitochondrial homeostasis in neurons-- mitostasis--are enigmatic and disease-prone, given a neurons large synaptic pool of mitochondria. To better understand mitostasis in mature mouse motor axons, we used ex vivo optical pulse-chase measurements of mitochondrial volume flux and identified a reiterative degradation system near presynaptic terminals and distal paranodes, which accounts for 75% of mitochondrial turnover in synapses. This distal filter system captures dysfunctional mitochondria from the retrograde stream and redirects them for lysosomal degradation. It depends on optineurin, a motor neuron disease-related mitophagy adaptor, but not on PINK1 and parkin, implicating a non-canonical mitophagy pathway. In presymptomatic motor neuron disease models, where retrograde transport is disrupted, the fraction of removed mitochondria is increased. Thus, we identify a new mitostasis system in distal axons with a cascade of checkpoints for local mitophagy, which normally maintains mitochondrial mass balance but is disrupted early in degenerative axonopathies.

cell biology↗

bioRxiv2024

Polyglutamylation of microtubules drives neuronal remodeling

Developmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. The cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a posttranslational tubulin modification that is enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation--TTLL glutamylases vs. CCP deglutamylases--accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as an activity-dependent rheostat of remodeling and shapes neuronal morphology and connectivity.

cell biology↗

bioRxiv2023

Intrinsic microtubule destabilization of multiciliated choroid plexus epithelial cells during postnatal lifetime

Choroid plexus (ChP) epithelium is composed of specialized multiciliated cells. By using multiple microscopic techniques, biochemical approaches in various mutant mice and longitudinal analysis from mouse embryogenesis to aging, we show that ChP cilia are built on a gradient of events which are spatio-temporally regulated. We uncover that ChP cilia develop prenatally since early tissue morphogenesis, and proceeds as a multi-step process characterized by basal body multiplication and axoneme formation directly at the apical cellular compartment. Our data also show that choroid plexus cilia contain both primary and motile features. Remarkably, we demonstrate that ChP cilia undergo axoneme resorption, starting from early youth, through a tubulin destabilization process, which is primarily controlled by polyglutamylation levels and could be mitigated by the removal of the microtubule-severing enzyme spastin. Notably, we demonstrate that this phenotype is preserved in human samples.

developmental biology↗

bioRxiv2019

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins is key to development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling and its dysfunction has been linked to schizophrenia, however, nothing is known about its role in the synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that while CRMP2 has only a moderate effect on Sema3A-dependent axon guidance in vivo, it is essential for Sema3F-dependent axon pruning and dendritic spine remodeling. We first demonstrate that CRMP2 deficiency interferes with Sema3A signaling in compartmentalized neuron cultures and leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. Strikingly, we show that crmp2-/- mice display more prominent defects in dendritic spine pruning and stereotyped axon pruning in hippocampus and visual cortex consistent with impaired Sema3F signaling and with autism spectrum disorder (ASD)-rather than schizophrenia-like phenotype. Indeed, we demonstrate that CRMP2 mediates Sema3F-induced axon retraction in primary neurons and that crmp2-/- mice display early postnatal behavioral changes linked to ASD. In conclusion, we demonstrate that CRMP2 is an essential mediator of Sema3F-dependent synapse pruning and its dysfunction in early postnatal stages shares histological and behavioral features of ASD.

neuroscience↗

bioRxiv2017

Programming of neural progenitors of the adult subependymal zone towards a glutamatergic identity by neurogenin2

While the adult subependymal zone (SEZ) harbors pools of distinct neural stem cells that generate different types of GABAergic interneurons, a small progenitor population in the dorsal SEZ expresses Neurog2 and gives rise to glutamatergic neurons. Here we investigated whether SEZ progenitors can be programmed towards glutamatergic neurogenesis through forced expression of Neurog2. Retrovirus-mediated expression of Neurog2 induced the glutamatergic neuron lineage markers Tbr2 and Tbr1 in cultured SEZ progenitors which subsequently differentiated into functional glutamatergic neurons. Likewise, retrovirus-mediated expression of Neurog2 in dividing SEZ progenitors within the adult SEZ induced Tbr2 and Tbr1 expression, hallmarking entry into the glutamatergic lineage also in vivo. Intriguingly, Neurog2-expressing progenitors failed to enter the rostral migratory stream (RMS) and instead differentiated directly within the SEZ or the adjacent striatum. In sharp contrast, lentivirus-mediated postmitotic expression of Neurog2 failed to reprogram early SEZ neurons, which instead maintained their GABAergic identity and migrated along the RMS towards the olfactory bulb. Thus, our data show that Neurog2 can program SEZ progenitors towards a glutamatergic identity, but fails to reprogram their postmitotic progeny.\n\nSummary statementOur study identifies a critical developmental time window during which progenitors of the adult subependymal zone, specified for generating GABAergic neurons, can be reprogrammed towards glutamatergic neurogenesis.

neuroscience↗