Biology subjects

Decker, S. C.

Publications and source records attributed to Decker, S. C..

3 recordsLinked to original sources

bioRxiv2026

Pannexin-1 channel activity regulates neurogenesis and cell survival in the developing cortex

Mutations in genes encoding a range of ion-conducting proteins disrupt development of the cerebral cortex in humans, often causing polymicrogyria (PMG); yet how ion conduction guides the development of cortical architecture is not clear. Here, we describe three individuals with brain malformations including PMG and microcephaly in whom de novo, missense mutations were identified in PANX1--encoding an ATP and ion conducting channel. We show that these PMG-associated PANX1 mutations (p.D14H, p.M37R, and p.N338T) disrupt normal glycosylation and confer gain-of-function with respect to ATP release and channel conductance. In vivo modeling of mutant PANX1 in cortical progenitor cells demonstrated disrupted cell migration and excess cell death in both mice and ferret models. In vitro modeling of the p.N338T allele in human induced pluripotent stem cell (hiPSC)-derived neurons further revealed changes in neuronal morphology and increased excitability, and dysregulation of key transcription factors critical for neurogenesis and cell fate. In addition, p.N338T iPSC-derived neural progenitor cells displayed increased PANX1 activation. Our results show that normal PANX1 function contributes to cortical structure through regulation of ion conductance and ATP release and provides insight into how these processes influence corticogenesis and cytoarchitecture more broadly.

neuroscience↗

bioRxiv2025

Uncoupling Neocortical Neuron Fate and Migration via a Let-7-RBX2 Axis

Throughout the central nervous system, the fate and migration of projection neurons are tightly coordinated to ensure that specific neuronal fates settle in precise spatial locations. This is particularly evident in the mammalian neocortex, where early-born projection neurons predominantly remain in the deeper layers of the cortical plate, whereas later-born neurons localize more superficially. However, it remains unclear whether neuronal fate acquisition directly primes the molecular mechanisms driving pyramidal neuron migration and positioning, or on the contrary fate and positioning are regulated independently. MicroRNAs have emerged as key regulators of cell fate determination in the neocortex. Among them, let-7 is known to influence neural progenitor competence and promote the neurogenesis of late-born projection neurons. Here, we show that let-7 also regulates projection neuron migration and positioning by targeting RBX2, a core component of the E3 ubiquitin ligase CRL5, which has been previously shown to inhibit neuron migration by terminating the Reelin/DAB1 signaling pathway. Let-7 directly binds to a conserved motif in the 3' UTR of RBX2, reducing its translation and thereby diminishing CRL5 activity. Importantly, restoring RBX2 levels in the context of let-7 overexpression rescues the positioning of pyramidal neurons without altering let-7-induced effects on neuronal fate. Furthermore, we demonstrate that let-7 enhances pyramidal neuron migration by increasing locomotion speed and prolonging migratory activity. Together, these findings reveal that let-7 coordinates neuronal fate specification and migration via distinct molecular pathways, ensuring the proper laminar positioning of late-born pyramidal neurons in the neocortex.

developmental biology↗

bioRxiv2022

Notch directs telencephalic development and neuron fate determination by regulating miRNA levels

The central nervous system (CNS) contains myriads of different types of cells produced from multipotent neural progenitors. Neural progenitors acquire distinct cell identities depending on their spatial position, but they are also influenced by temporal cues to give rise to different cell populations over time. For instance, the progenitors of the cerebral neocortex generate different populations of excitatory projection neurons following a well-known sequence. The Notch signaling pathway plays crucial roles this process but the molecular mechanisms by which Notch impacts progenitor fate decisions have not been fully resolved. Here, we show that Notch signaling is essential for neocortical and hippocampal morphogenesis, and for the development of the corpus callosum and choroid plexus. Our data also indicate that, in the neocortex, Notch controls projection neuron fate determination through the regulation of two microRNA (miRNA) clusters that include let-7, miR-99a/100, and miR-125b. Our findings collectively suggest that balanced Notch signaling is crucial for telencephalic development and that the interplay between Notch and miRNAs is critical to control neocortical progenitor behaviors and neuron cell fate decisions.

developmental biology↗