Biology subjects

Fuerst, P. G.

Publications and source records attributed to Fuerst, P. G..

3 recordsLinked to original sources

bioRxiv2025

Neurons maintain sequential order during radial migration by DSCAM-facilitated antagonism of N-Cadherin

Proper radial migration of developing cortical neurons is critical for the "inside-out" laminar organization of the mammalian cerebral cortex. While substantial progress has been made in our understanding of how neurons terminate migration at the cortical plate (CP)/marginal layer (ML) boundary, the mechanisms that control the sequential order of migrating neurons remain poorly understood. Here, we show that radial migration of upper-layer pyramidal neurons is transiently restrained within the upper cortical plate (UCP), where migrating neurons assemble into vertically organized radial queues that maintain inter-neuronal spacing and migratory order. Using time-lapse imaging of embryonic mouse cortex, we found that leading neurons transiently delay nucleokinesis of trailing neurons, thereby synchronizing neuronal movement within the UCP. Loss of Down syndrome cell adhesion molecule (DSCAM) disrupts this coordinated migratory behavior, allowing trailing neurons to bypass preceding neurons, resulting in abnormal neuronal accumulation near the CP/ML boundary. Mechanistically, DSCAM localizes to membrane interfaces between adjacent migrating neurons. At these sites, DSCAM suppresses N-cadherin-mediated intercellular adhesion, limits F-actin assembly, and inhibits expansion of the proximal cytoplasmic dilation required for nucleokinesis. Dscam-deficient neurons exhibit increased cadherin puncta, more neuron-neuron contacts, and accelerated migration through the UCP. Rescue experiments demonstrate that expressing the extracellular domain of Dscam is sufficient to restore ordered migration, suggesting that an extracellular mechanism regulates orderly neuronal migration. In addition, we identify UNC5c-mediated signaling as a counterbalancing force that promotes upward migration within the UCP. Together, our findings identify radial neuronal queues as a previously unrecognized intermediate structure in cortical morphogenesis and establish DSCAM-dependent regulation of inter-neuronal spacing as a mechanism that preserves the migratory order during inside-out corticogenesis.

developmental biology↗

bioRxiv2020

Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma. One Sentence SummaryThe NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.

neuroscience↗

bioRxiv2020

Dscam gene triplication causes neocortical overinhibition in Down syndrome

A growing number of molecules have been identified as regulators of inhibitory synapse development, but whether dysregulated expression of these molecules contribute to brain disorders is poorly understood. Here we show that Down syndrome cell adhesion molecule (Dscam) regulates the inhibition of neocortical pyramidal neurons (PyNs) in a level-dependent fashion. Loss of Dscam impairs inhibitory neuron development and function. In the Ts65Dn mouse model for Down syndrome, where Dscam is overexpressed, GABAergic innervation of cortical PyNs by chandelier and basket cells is increased. Genetic normalization of Dscam expression rescues the excessive GABAergic innervation and the increased inhibition of PyNs. These findings demonstrate excessive GABAergic innervation and inhibition in the neocortex of Down syndrome mouse model and identify Dscam overexpression as the cause. They also implicate dysregulated Dscam levels as a potential pathogenic driver in related neurological disorders.

neuroscience↗