Biology subjects

McQueen, J. P.

Publications and source records attributed to McQueen, J. P..

3 recordsLinked to original sources

bioRxiv2026

Human neuromodulatory assembloids to study serotonin signaling and disease

Neuromodulators influence critical functions of the developing human brain and regulate behavioral states. Dysfunction of neuromodulatory systems is often involved in neuropsychiatric disease and many drugs for these conditions act on these signaling pathways. Recent advances in stem cell biology have made it possible to derive a wide range of cells across the developing human nervous system in regionalized organoids and to functionally integrate them into assembloids, however they currently do not systematically incorporate neuromodulation. Here, we generated human midbrain-hindbrain organoids (hMHO) from human induced pluripotent stem (hiPS) cells and fused them with human cortical organoids (hCO) to form neuromodulatory assembloids (hNMA). We focus on serotonin (5-hydroxytryptamine, 5-HT) as one key neuromodulator and found characteristic gene expression patterns and electrophysiological properties of serotonergic neurons (5-HT neurons) in the hMHO. In hNMA, 5-HT neurons projected into hCO, released 5-HT and modulated cortical network activity. To explore the applicability of this system in human disease, we studied 22q11.2 deletion syndrome (22q11.2DS), a common microdeletion associated with high risk for neuropsychiatric disease and defects in 5-HT signaling. We found aberrant 5-HT dynamics in hNMA from patient hiPS cell lines that were rescued by administration of a selective serotonin reuptake inhibitor (SSRI). Taken together, hNMA can be used to study human 5-HT dynamics and uncover disease phenotypes which could facilitate therapeutic development.

neuroscience↗

bioRxiv2024

Midline Assembloids Reveal Regulators of Human Axon Guidance

Organizers are specialized cell populations that orchestrate cell patterning and axon guidance in the developing nervous system. Although non-human models have led to fundamental discoveries about the organization of the nervous system midline by the floor plate, an experimental model of human floor plate would enable broader insights into regulation of human neurodevelopment and midline connectivity. Here, we have developed stem cell-derived organoids resembling human floor plate (hFpO) and assembled them with spinal cord organoids (hSpO) to generate midline assembloids (hMA). We demonstrate that hFpO promote Sonic hedgehog-dependent ventral patterning of human spinal progenitors and Netrin-dependent guidance of human commissural axons, paralleling non-human models. To investigate evolutionary-divergent midline regulators, we profiled the hFpO secretome and identified 27 evolutionarily divergent genes between human and mouse. Utilizing the hMA platform, we targeted these candidates in an arrayed CRISPR knockout screen and reveal that GALNT2, a gene involved in O-linked glycosylation, impairs floor plate-mediated guidance of commissural axons in humans. This novel platform extends prior axon guidance discoveries into human-specific neurobiology with implications for mechanisms of nervous system evolution and neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

Kirigami electronics for long-term electrophysiological recording of human neural organoids and assembloids

Organoids and assembloids have emerged as a promising platform to model aspects of nervous system development. Longterm, minimally-invasive recordings in these multi-cellular systems are essential for developing disease models. Current technologies, such as patch-clamp, penetrating microelectrodes, planar electrode arrays and substrate-attached flexible electrodes, do not, however, allow chronic recording of organoids in suspension, which is necessary to preserve their architecture. Inspired by the art of kirigami, we developed flexible electronics that transition from a 2D pattern to a 3D basketlike configuration to accommodate the long-term culture of organoids in suspension. This platform, named kirigami electronics (KiriE), integrates with and enables chronic recording of cortical organoids while preserving morphology, cytoarchitecture, and cell composition. KiriE can be integrated with optogenetic and pharmacological stimulation and model disease. Moreover, KiriE can capture activity in cortico-striatal assembloids. Moving forward, KiriE could reveal disease phenotypes and activity patterns underlying the assembly of the nervous system.

neuroscience↗