Biology subjects

Veling, M. W.

Publications and source records attributed to Veling, M. W..

4 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

isoTarget: a genetic method for analyzing the functional diversity of splicing isoforms in vivo

Protein isoforms generated by alternative splicing contribute to proteome diversity. Due to the lack of effective techniques, isoform-specific functions, expression, localization, and signaling mechanisms of endogenous proteins in vivo are unknown for most genes. Here we report a genetic method, termed isoTarget, for blocking the expression of a targeted isoform without affecting the other isoforms and for conditional tagging the targeted isoform for multi-level analyses in select cells. Applying isoTarget to two mutually exclusive isoforms of Drosophila Dscam, Dscam[TM1] and [TM2], we found that endogenous Dscam[TM1] is localized in dendrites while Dscam[TM2] is in both dendrites and axons. We demonstrate that the difference in subcellular localization between Dscam[TM1] and [TM2], rather than any difference in biochemical properties, leads to the two isoforms differential contributions to dendrite and axon development. Moreover, with isoTarget, we discovered that the subcellular enrichment of functional partners results in a DLK/Wallenda-Dscam[TM2]-Dock signaling cascade specifically in axons. isoTarget is an effective technique for studying how alternative splicing enhances proteome complexity.

genetics↗

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↗

bioRxiv2019

Identification of neuronal lineages in the Drosophila peripheral nervous system with a novel multi-spectral lineage tracing system

Elucidating cell lineages provides crucial understanding of development. Recently developed sequencing-based techniques enhance the scale of lineage tracing but eliminate the spatial information offered by conventional approaches. Multispectral labeling techniques, such as Brainbow, have the potential to identify lineage-related cells in situ. Here, we report Lineage Tracker Bitbow, a \"digital\" version of Brainbow that greatly expands the color diversity, and a suite of statistical methods for quantifying the lineage relationship of any two cells. Applying these tools to Drosophila peripheral nervous system, we determined lineage relationship between all neuronal pairs. Based on the refined lineage map, we explored whether distinct cis-regulatory elements are used in controlling the expression of a terminal selector gene in distinct lineage patterns. This study demonstrates LT-Bitbow as an efficient tool for in-situ lineage mapping and its potential in studying molecular mechanisms in the lineage context.

neuroscience↗