Shotelersuk, V. | bioRxiv Science

bioRxiv2025

Dopaminergic neurons are vulnerable to dysregulation of YEATS2-dependent calcium homeostasis

YEATS2 is a ubiquitously expressed chromatin-associated factor that we recently identified as a novel regulator of dopaminergic (DAergic) synaptic integrity, though its mechanism of action remained unclear. Using Drosophila, we show that neuronal depletion of YEATS2 reshapes the brain transcriptome, marked by downregulation of metabolic genes and upregulation of G protein-coupled receptors (GPCRs). These changes coincide with elevated intracellular calcium, neurobehavioral deficits, and selective DA neuron loss. Importantly, genetic or pharmacological inhibition of the store-operated calcium entry channel Orai restored calcium homeostasis and rescued DA neuron survival. Our findings define a YEATS2-dependent epigenetic-calcium axis that governs DA neuron vulnerability.

neuroscience↗

bioRxiv2018

Mutations in Kinesin Family Member 6 Reveal Specific Role in Ependymal Cell Function and Human Neuro-Cranial Development

Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurocranial defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cell (EC) layer of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed a reduction in EC cilia, without effect on other multiciliated tissues. Consistent with our findings in mice, defects of the ventricular system and EC cilia were observed in kif6 mutant zebrafish. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neuro-cranial morphogenesis with a specific role in the maintenance of EC cilia in vertebrates.\n\nAUTHOR SUMMARYCerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain. Localized flows of cerebrospinal fluid throughout the ventricular system of the brain are established from the polarized beating of the ependymal cell (EC) cilia. Here, we identified a homozygous truncating mutation in KIF6 in a child displaying neuro-cranial defects and intellectual disability. To test the function of KIF6 in vivo, we engineered mutations of Kif6 in mouse. These Kif6 mutant mice display severe hydrocephalus, coupled with a loss of EC cilia. Similarly, we observed hydrocephalus and a reduction in EC cilia in kif6 mutant zebrafish. Overall, this work describes the first clinically-defined KIF6 mutation in human, while our animal studies demonstrate the pathogenicity of mutations in KIF6 and establish KIF6 as a conserved mediator of neuro-cranial development and EC cilia maintenance in vertebrates.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC=\"FIGDIR/small/350140_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (58K):\norg.highwire.dtl.DTLVardef@d36bc6org.highwire.dtl.DTLVardef@48cbfborg.highwire.dtl.DTLVardef@147e273org.highwire.dtl.DTLVardef@641ce3_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗