scholarly journals Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1284
Author(s):  
Rasem Mustafa ◽  
Chahinaz Rawas ◽  
Nadja Mannal ◽  
Grzegorz Kreiner ◽  
Björn Spittau ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Primary Cilia ◽  
Critical Role ◽  
Metabolic Stress ◽  
Relative Number ◽  
Dopamine System ◽  
Adult Mice ◽  
Metabolic Conditions ◽  
Molecular Signals

Primary cilia (PC) are microtubule-based protrusions of the cell membrane transducing molecular signals during brain development. Here, we report that PC are required for maintenance of Substantia nigra (SN) dopaminergic (DA) neurons highly vulnerable in Parkinson’s disease (PD). Targeted blockage of ciliogenesis in differentiated DA neurons impaired striato-nigral integrity in adult mice. The relative number of SN DA neurons displaying a typical auto-inhibition of spontaneous activity in response to dopamine was elevated under control metabolic conditions, but not under metabolic stress. Strikingly, in the absence of PC, the remaining SN DA neurons were less vulnerable to the PD neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP). Our data indicate conserved PC-dependent neuroadaptive responses to DA lesions in the striatum. Moreover, PC control the integrity and dopamine response of a subtype of SN DA neurons. These results reinforce the critical role of PC as sensors of metabolic stress in PD and other disorders of the dopamine system.

scholarly journals Primary cilia respond to intermittent low-magnitude, high-frequency vibration and mediate vibration-induced effects in osteoblasts

2020 ◽  
Vol 318 (1) ◽  
pp. C73-C82 ◽  
Author(s):  
Yan-Hui Li ◽  
Dong Zhu ◽  
Zongbing Cao ◽  
Yanwei Liu ◽  
Jian Sun ◽  
...  
Keyword(s):  
Western Blot ◽  
Blot Analysis ◽  
High Frequency ◽  
Western Blot Analysis ◽  
Primary Cilia ◽  
Critical Role ◽  
Rt Pcr ◽  
High Frequency Vibration ◽  
Low Magnitude

Our objective was to investigate the role of primary cilia in low-magnitude, high-frequency vibration (LMHFV) treatment of MC3T3-E1 osteoblasts (OBs). We used chloral hydrate (CH), which has a well-characterized function in chemically removing primary cilia, to elucidate the role of primary cilia in LMHFV-induced OB osteogenic responses through cell viability assay, Western blot analysis, real-time quantitative RT-PCR, and histochemical staining methods. We observed a significant, 30% decrease in the number of MC3T3-E1 OBs with primary cilia (reduced from 64.3 ± 5%) and an approximately 50% reduction in length of primary cilia (reduced from 3 ± 0.8 μm) after LMHFV stimulation. LMHFV stimulation upregulated protein expression of the bone matrix markers collagen 1 (COL-1), osteopontin (OPN), and osteoclacin(OCN) in MC3T3-E1 OBs, indicating that LMHFV induces osteogenesis. High-concentration or long-duration CH exposure resulted in inhibition of MC3T3-E1 OB survival. In addition, Western blot analysis and RT-PCR revealed that CH treatment prevented LMHFV-induced osteogenesis. Furthermore, decreased alkaline phosphate activity, reduced OB differentiation, mineralization, and maturation were observed in CH-pretreated and LMHFV-treated OBs. We showed that LMHFV induces morphological changes in primary cilia that may fine-tune their mechanosensitivity. In addition, we demonstrated the significant inhibition by CH of LMHFV-induced OB mineralization, maturation, and differentiation, which might reveal the critical role of primary cilia in the process.

scholarly journals Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice

2018 ◽  
Vol 115 (51) ◽  
pp. 13105-13110 ◽  
Author(s):  
Hongsheng Wang ◽  
Fang Liu ◽  
Wenbing Chen ◽  
Xiangdong Sun ◽  
Wanpeng Cui ◽  
...  
Keyword(s):  
Neural Development ◽  
Critical Role ◽  
Gaba Release ◽  
Brain Disorders ◽  
Gabaergic Transmission ◽  
Brain Functions ◽  
Adult Mice ◽  
Mutant Strains ◽  
And Behavior

Neurotrophic factor NRG1 and its receptor ErbB4 play a role in GABAergic circuit assembly during development. ErbB4 null mice possess fewer interneurons, have decreased GABA release, and show impaired behavior in various paradigms. In addition, NRG1 and ErbB4 have also been implicated in regulating GABAergic transmission and plasticity in matured brains. However, current ErbB4 mutant strains are unable to determine whether phenotypes in adult mutant mice result from abnormal neural development. This important question, a glaring gap in understanding NRG1–ErbB4 function, was addressed by using two strains of mice with temporal control of ErbB4 deletion and expression, respectively. We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology. On the other hand, some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate a critical role of NRG1–ErbB4 signaling in GABAergic transmission and behavior in adulthood and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders.

scholarly journals The Ciliopathy Gene Ftm/Rpgrip1l Controls Mouse Forebrain Patterning via Region-Specific Modulation of Hedgehog/Gli Signaling

2018 ◽  
Author(s):  
Abraham Andreu-Cervera ◽  
Isabelle Anselme ◽  
Alice Karam ◽  
Martin Catala ◽  
Sylvie Schneider-Maunoury
Keyword(s):  
Sonic Hedgehog ◽  
Primary Cilia ◽  
System Development ◽  
Critical Role ◽  
Ground Level ◽  
Nervous System Development ◽  
Gli Transcription Factors ◽  
Optic Vesicles ◽  
Specific Control

ABSTRACTPrimary cilia are essential for central nervous system development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rgprip1l ciliopathy gene is disrupted. At the end of gestation, Ftm-/- fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm-/- embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. We analyzed the molecular causes of these defects. In Ftm-/- embryos, Sonic hedgehog (Shh) expression was lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. In the diencephalon, Gli activity was dampened in regions adjacent to the Shh-expressing ZLI but displayed a higher Hh-independent ground level in the other regions. Our data uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects.

scholarly journals The critical role of Hedgehog-responsive mesenchymal progenitors in meniscus development and injury repair

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yulong Wei ◽  
Hao Sun ◽  
Tao Gui ◽  
Lutian Yao ◽  
Leilei Zhong ◽  
...  
Keyword(s):  
Critical Role ◽  
Cartilage Degeneration ◽  
Repair Process ◽  
Superficial Layer ◽  
Mesenchymal Progenitors ◽  
Adult Mice ◽  
Meniscal Tissue ◽  
New Treatment ◽  
Meniscal Cells

Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using a Gli1 reporter line, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1-lineage cells. Normally, meniscal tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh agonist right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.

scholarly journals Targeting Oncogene-Induced Autophagy: A New Approach in Cancer Therapy?

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Fuquan Zhang ◽  
Jit Kong Cheong
Keyword(s):  
Cancer Progression ◽  
Cell Transformation ◽  
Critical Role ◽  
Metabolic Stress ◽  
Degradation Process ◽  
Therapeutic Benefit ◽  
Proper Function ◽  
Cell Integrity ◽  
Growth And Survival

Autophagy is a tightly controlled self-degradation process utilised by cells to sustain cellular homeostasis and to support cell survival in response to metabolic stress and starvation. Thus, autophagy plays a critical role in promoting cell integrity and maintaining proper function of cellular processes. Defects in autophagy, however, can have drastic implications in human health and diseases, including cancer. Described as a double-edged sword in the context of cancer, autophagy can act as both suppressor and facilitator of tumorigenesis. As such, defining the precise role of autophagy in a multistep event like cancer progression can be complex. Recent findings have implicated a role for components of the autophagy pathway in oncogene-mediated cell transformation, tumour growth, and survival. Notably, aggressive cancers driven by Ras oncoproteins rely on autophagy to sustain a reprogrammed mitochondrial metabolic signature and evade cell death. In this review, we summarize our current understanding of the role of oncogene-induced autophagy in cancer progression and discuss how modulators of autophagic responses can bring about therapeutic benefit and eradication of a subset of cancers that are addicted to this ancient recycling machinery.

Critical role of FLT3 ligand in IL-7 receptor–independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2955-2964 ◽  
Author(s):  
Ewa Sitnicka ◽  
Natalija Buza-Vidas ◽  
Henrik Ahlenius ◽  
Corrado M. Cilio ◽  
Christos Gekas ◽  
...  
Keyword(s):  
Critical Role ◽  
Molecular Pathways ◽  
Flt3 Ligand ◽  
Interleukin 7 ◽  
Adult Mice ◽  
Multipotent Progenitors ◽  
Deficient Mice ◽  
Adult Thymus ◽  
T Lymphopoiesis

Abstract The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)–deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor α (IL-7Rα) signaling. Fl−/−Il-7r−/− mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Rα–independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Rα, in regulation of the earliest lineage-negative (Lin−) Lin−SCA1+KIT+ (LSK) FLT3hi lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.

scholarly journals Dopamine promotes aggression in mice via ventral tegmental area to lateral septum projections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Darshini Mahadevia ◽  
Rinki Saha ◽  
Alessia Manganaro ◽  
Nao Chuhma ◽  
Annette Ziolkowski-Blake ◽  
...  
Keyword(s):  
Aggressive Behavior ◽  
Ventral Tegmental Area ◽  
Dopaminergic Neurons ◽  
D2 Receptors ◽  
Gabaergic Neurons ◽  
Lateral Septum ◽  
Dopamine System ◽  
Dopaminergic Activity ◽  
Ventral Tegmental

AbstractSeptal-hypothalamic neuronal activity centrally mediates aggressive behavior and dopamine system hyperactivity is associated with elevated aggression. However, the causal role of dopamine in aggression and its target circuit mechanisms are largely unknown. To address this knowledge gap, we studied the modulatory role of the population- and projection-specific dopamine function in a murine model of aggressive behavior. We find that terminal activity of ventral tegmental area (VTA) dopaminergic neurons selectively projecting to the lateral septum (LS) is sufficient for promoting aggression and necessary for establishing baseline aggression. Within the LS, dopamine acts on D2-receptors to inhibit GABAergic neurons, and septal D2-signaling is necessary for VTA dopaminergic activity to promote aggression. Collectively, our data reveal a powerful modulatory influence of dopaminergic synaptic input on LS function and aggression, effectively linking the clinically pertinent hyper-dopaminergic model of aggression with the classic septal-hypothalamic aggression axis.

scholarly journals Dlec1 is required for spermatogenesis and male fertility in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu Okitsu ◽  
Mamoru Nagano ◽  
Takahiro Yamagata ◽  
Chizuru Ito ◽  
Kiyotaka Toshimori ◽  
...  
Keyword(s):  
Male Fertility ◽  
Primary Cilia ◽  
Critical Role ◽  
Intraflagellar Transport ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Adenocarcinoma Cells ◽  
Cilia Formation ◽  
Ring Complex

Abstract Deleted in lung and esophageal cancer 1 (DLEC1) is a tumour suppressor gene that is downregulated in various cancers in humans; however, the physiological and molecular functions of DLEC1 are still unclear. This study investigated the critical role of Dlec1 in spermatogenesis and male fertility in mice. Dlec1 was significantly expressed in testes, with dominant expression in germ cells. We disrupted Dlec1 in mice and analysed its function in spermatogenesis and male fertility. Dlec1 deletion caused male infertility due to impaired spermatogenesis. Spermatogenesis progressed normally to step 8 spermatids in Dlec1−/− mice, but in elongating spermatids, we observed head deformation, a shortened tail, and abnormal manchette organization. These phenotypes were similar to those of various intraflagellar transport (IFT)-associated gene-deficient sperm. In addition, DLEC1 interacted with tailless complex polypeptide 1 ring complex (TRiC) and Bardet–Biedl Syndrome (BBS) protein complex subunits, as well as α- and β-tubulin. DLEC1 expression also enhanced primary cilia formation and cilia length in A549 lung adenocarcinoma cells. These findings suggest that DLEC1 is a possible regulator of IFT and plays an essential role in sperm head and tail formation in mice.

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