Browsing by Author "Chen, Jiang"

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    A cell–ECM mechanism for connecting the ipsilateral eye to the brain
    Su, Jianmin; Sabbagh, Ubadah; Liang, Yanping; Olejníková, Lucie; Dixon, Karen G.; Russell, Ashley L.; Chen, Jiang; Pan, Yuchin Albert; Triplett, Jason W.; Fox, Michael A. (National Academy of Sciences, 2021-10-15)
    Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.
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    Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex
    Su, Jianmin; Chen, Jiang; Lippold, Kumiko; Monavarfeshani, Aboozar; Carrillo, Gabriela Lizana; Jenkins, Rchael; Fox, Michael A. (Rockefeller University Press, 2016-03-14)
    Inhibitory synapses comprise only ∼20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen—collagen XIX—in the formation of Parvalbumin+ inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses.
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    Modulation of gap junction-associated Cx43 in neural stem/progenitor cells following traumatic brain injury
    Greer, Kisha; Chen, Jiang; Brickler, Thomas; Gourdie, Robert G.; Theus, Michelle H. (2017-09)
    Restoration of learning and memory deficits following traumatic brain injury (TBI) is attributed, in part, to enhanced neural stem/progenitor cell (NSPCs) function. Recent findings suggest gap junction (GJ)-associated connexin 43 (Cx43) plays a key role in the cell cycle regulation and function of NSPCs and is modulated following TBI. Here, we demonstrate that Cx43 is up-regulated in the dentate gyrus following TBI and is expressed on vimentin-positive cells in the subgranular zone. To test the role of Cx43 on NSPCs, we exposed primary cultures to the alpha-connexin Carboxyl Terminal (alpha CT1) peptide which selectively modulates GJ-associated Cx43. Treatment with alpha CT1 substantially reduced proliferation and increased caspase 3/7 expression on NSPCs in a dose-dependent manner. alpha CT1 exposure also reduced overall expression of Cx43 and phospho (p)-Serine368. These findings demonstrate that Cx43 positively regulates adult NPSCs; the modulation of which may influence changes in the dentate gyrus following TBI.
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    Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage
    Kowalski, Elizabeth A.; Chen, Jiang; Hazy, Amanda; Fritsch, Lauren E.; Gudenschwager-Basso, Erwin K.; Chen, Michael; Wang, Xia; Qian, Yun; Zhou, Mingjun; Byerly, Matthew; Pickrell, Alicia M.; Matson, John B.; Allen, Irving C.; Theus, Michelle H. (2019-11-11)
    Background The continuum of pro- and anti-inflammatory response elicited by traumatic brain injury (TBI) is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain ill -defined. Methods Here, we demonstrate that using bone marrow chimeric mice and systemic inhibition of EphA4 receptor shifts the pro-inflammatory milieu to pro-resolving following acute TBI. Results EphA4 expression is increased in the injured cortex as early as 2 h post-TBI and on CX3CR1gfp-positive cells in the peri-lesion. Systemic inhibition or genetic deletion of EphA4 significantly reduced cortical lesion volume and shifted the inflammatory profile of peripheral-derived immune cells to pro-resolving in the damaged cortex. These findings were consistent with in vitro studies showing EphA4 inhibition or deletion altered the inflammatory state of LPS-stimulated monocyte/macrophages towards anti-inflammatory. Phosphoarray analysis revealed that EphA4 may regulate pro-inflammatory gene expression by suppressing the mTOR, Akt, and NF-κB pathways. Our human metadata analysis further demonstrates increased EPHA4 and pro-inflammatory gene expression, which correlates with reduced AKT concurrent with increased brain injury severity in patients. Conclusions Overall, these findings implicate EphA4 as a novel mediator of cortical tissue damage and neuroinflammation following TBI.
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    Type I Interferon Response Is Mediated by NLRX1-cGAS-STING Signaling in Brain Injury
    Fritsch, Lauren E.; Ju, Jing; Basso, Erwin Kristobal Gudenschwager; Soliman, Eman; Paul, Swagatika; Chen, Jiang; Kaloss, Alexandra M.; Kowalski, Elizabeth A.; Tuhy, Taylor C.; Somaiya, Rachana Deven; Wang, Xia; Allen, Irving C.; Theus, Michelle H.; Pickrell, Alicia M. (Frontiers, 2022-02-25)
    Background: Inflammation is a significant contributor to neuronal death and dysfunction following traumatic brain injury (TBI). Recent evidence suggests that interferons may be a key regulator of this response. Our studies evaluated the role of the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) signaling pathway in a murine model of TBI. Methods: Male, 8-week old wildtype, STING knockout (−/−), cGAS−/−, and NLRX1−/− mice were subjected to controlled cortical impact (CCI) or sham injury. Histopathological evaluation of tissue damage was assessed using non-biased stereology, which was complemented by analysis at the mRNA and protein level using qPCR and western blot analysis, respectively. Results: We found that STING and Type I interferon-stimulated genes were upregulated after CCI injury in a bi-phasic manner and that loss of cGAS or STING conferred neuroprotection concomitant with a blunted inflammatory response at 24 h post-injury. cGAS−/− animals showed reduced motor deficits 4 days after injury (dpi), and amelioration of tissue damage was seen in both groups of mice up to 14 dpi. Given that cGAS requires a cytosolic damage- or pathogen-associated molecular pattern (DAMP/PAMP) to prompt downstream STING signaling, we further demonstrate that mitochondrial DNA is present in the cytosol after TBI as one possible trigger for this pathway. Recent reports suggest that the immune modulator NLR containing X1 (NLRX1) may sequester STING during viral infection. Our findings show that NLRX1 may be an additional regulator that functions upstream to regulate the cGAS-STING pathway in the brain. Conclusions: These findings suggest that the canonical cGAS-STING-mediated Type I interferon signaling axis is a critical component of neural tissue damage following TBI and that mtDNA may be a possible trigger in this response.