Biology subjects

Schoepf, C. L.

Publications and source records attributed to Schoepf, C. L..

3 recordsLinked to original sources

bioRxiv2023

IL-4 shaping glutamatergic synapse like structures for more mature iPSC derived neuron phenotypes

The prototypical pleiotropic anti-inflammatory cytokine IL-4 not only acts on immune cells but also has important roles in the nervous system mediating antinociception and neuroregeneration. Therefore, we explored the expression of IL-4, its receptors IL4RA and IL13RA1 and downstream signaling components together with morphological and functional assays as well as transcriptomic profiling in human nociceptors differentiating from induced pluripotent stem cells (iNocs). IL-4 induced de novo formation of synaptic boutons immunoreactive for vesicular glutamate transporter vGLUT1 in iNocs which express both, components of the IL-4 receptor complex (IL-4RA and IL-13RA1) and signaling machinery (Jak1/2, STAT6, PKC isoforms, translation factor EiF4E) during differentiation. Pharmacological inhibition of these translational or cellular signaling components reduced the synaptogenic effect. IL-4 induced distinct transcriptomic changes associated with biological process ontologies for "neuron projection development", "axonogenesis" and "synapse", "cellular process involved in reproduction in multicellular organism", "regulation of membrane potential" and "calcium ion transmembrane transport". This partially reflected injury-induced transcriptional changes of mouse nerve injury models which contribute to regenerative processes in peripheral nerve but possibly also to reconnecting primary afferent neurons to their projections in the spinal dorsal horn and indicates a critical role for IL-4 in the control of developing and established neuronal networks.

neuroscience↗

bioRxiv2021

NOCICEPTRA: Gene and microRNA signatures and their trajectories characterizing human iPSC-derived nociceptor maturation

Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders. Since native human nociceptors are hardly available for mechanistic functional research, and rodent models do not necessarily mirror human pathologies in all aspects, human iPSC-derived nociceptors (iDN) offer superior advantages as a human model system. Unbiased mRNA::microRNA co-sequencing, immunofluorescence staining and qPCR validations, revealed expression trajectories as well as miRNA target spaces throughout the transition of pluripotent cells into iDNs. mRNA and miRNA candidates emerged as regulatory hubs for neurite outgrowth, synapse development and ion channel expression. The exploratory data analysis tool NOCICEPTRA is provided as a containerized platform to retrieve experimentally determined expression trajectories, and to query custom gene sets for pathway and disease enrichments. Querying NOCICEPTRA for marker genes of cortical neurogenesis revealed distinct similarities and differences for cortical and peripheral neurons. The platform provides a public domain neuroresource to exploit the entire data sets and explore miRNA and mRNA as hubs regulating human nociceptor differentiation and function.

neuroscience↗

bioRxiv2019

Presynaptic α2δ subunits are key organizers of glutamatergic synapses

In nerve cells the genes encoding for 2{delta} subunits of voltage-gated calcium channels (VGCCs) have been linked to synaptic functions and neurological disease. Here we show that 2{delta} subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular 2{delta} subunit triple loss-of-function model, we demonstrate a failure in presynaptic differentiation associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of 2{delta} isoforms as synaptic organizers is highly redundant, as each individual 2{delta} isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Mutating the MIDAS site in 2{delta}-2 dissociates rescuing presynaptic synapsin expression from calcium channel trafficking, suggesting that the regulatory role of 2{delta} subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. Firstly, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Secondly, the dependence of presynaptic differentiation on 2{delta} implicates 2{delta} subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that 2{delta} subunits act as trans-synaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.

neuroscience↗