Abstract
Primary cilia are centriole-derived sensory organelles that are present in most mammalian cells, including astrocytes and neurons. Evidence is emerging that astrocyte and neuronal primary cilia demonstrate a dichotomy in the mature mouse brain. However, it is unknown how astrocytic and neuronal primary cilia change their morphology and ciliary proteins when exposed to reactive insults including epilepsy and traumatic brain injury. We used a double transgenic mouse strain (Arl13b-mCherry; Centrin2-GFP), in which we found spontaneous seizures, and a cortical injury model to examine the morphological changes of astrocytic and neuronal primary cilia under reactive conditions. Transgenic overexpression of Arl13b drastically increases the length of astrocytic and neuronal primary cilia in the hippocampus, as well as the cilia lengths of cultured astrocytes and neurons. Spontaneous seizures shorten Arl13b-positive astrocytic cilia and AC3-positive neuronal cilia in the hippocampus. In a cortical injury model, Arl13b is not detectable in primary cilia, but Arl13b protein relocates to the cell body and has robust expression in the proximity of injured tissues. In contrast, the number of AC3-positive cilia near injured tissues remains unchanged, but their lengths become shorter. These results on astrocytic cilia implicate Arl13b in regulating astrocyte proliferation and tissue regeneration, while the shortening of AC3-positive cilia suggests adaptive changes of neuronal primary cilia under excitotoxicity.
Highlights
Primary cilia are microtubule-based sensory organelles present in most mammalian cells, including neurons and astrocytes in the brain [1, 2]
We focused on the cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and dentate gyrus (DG) regions in the hippocampus and measured cilia length in the three regions
Cilia number: Arl mice, 50; C57BL/6 mice, 57. m Cumulative distribution frequency plots (CDFs) and density comparisons demonstrate the differences in ADP-ribosylation factorlike protein 13b (Arl13b)-positive cilia length between Arl mice and C57BL/6 mice. n AC3-positive cilia in primarily cultured cortical neurons (~ 10 days in vitro) were significantly longer than those derived from C57BL/6 mice (***, p < 0.001, unpaired Student’s t-test)
Summary
Primary cilia are microtubule-based sensory organelles present in most mammalian cells, including neurons and astrocytes in the brain [1, 2]. Primary cilia are exquisitely sensitive to extracellular signals, serving as a hub to integrate signals to modulate a variety of cellular functions including neuronal activity [2, 4, 5]. Primary cilia have two diverged classes of function: to serve as the “cell antenna” [2, 7] to detect extracellular signals and to function as the “keeper of the key for cell division” [3] to regulate mitosis. Primary cilia play critical roles in sensory perception, and detection of neurotransmitters and hormones, regulation of cell division, development, and tissue regeneration [8,9,10,11]. Little is known about the physiological and pathological function of neuronal and astrocytic primary cilia, despite their strong association with many human diseases
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