Activity-dependent Regulation of the Choroid Plexus-Cerebrospinal Fluid Stem Cell Niche

脉络丛-脑脊液干细胞生态位的活动依赖性调节

• 批准号: 10626875
• 负责人: MARIA LEHTINEN
• 金额: $ 64.31万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626875
• 关键词: Affect; Agonist; Apical; Axon; Bathing; Brain; Brain Stem; Calcium; Cells; Cerebral cortex; Cerebrospinal Fluid; Choroid Plexus Epithelium; Couples; Cues; Data; Development; Diffusion; Embryo; Embryonic Development; Environment; Epithelial Cells; Epithelium; Fetal health; Future; G-Protein-Coupled Receptors; Gene Expression; Gene Proteins; Genetic; Genetic Transcription; Growth; Health; Image; Immediate-Early Genes; In Vitro; Intraperitoneal Injections; Investigation; Ligands; Mediating; Methods; Modernization; Molecular; Monitor; Mus; Nature; Neurodevelopmental Disorder; Neurologic; Neurons; Penetrance; Peripheral; Phenotype; Placenta; Process; Production; Protein Secretion; Receptor Activation; Receptor Signaling; Regulation; Salivary Glands; Serotonin; Signal Pathway; Signal Transduction; Source; Stimulus; Structure of choroid plexus; Surface; Testing; brain tissue; direct application; experimental study; fetal; gene induction; in vivo; in vivo calcium imaging; intraperitoneal; loss of function; nerve stem cell; neurosteroids; novel; postnatal; receptor; response; stem cell niche; tool; transcriptome; transcriptome sequencing; transcriptomics; vesicular release

PROJECT SUMMARY / ABSTRACT Building the cerebral cortex requires the spatial and temporal orchestration of molecular signals across neural progenitor cells. Each of these cells is bathed in cerebrospinal fluid (CSF), a medium rich in health- and growth- promoting factors whose composition changes profoundly across days during brain development. The choroid plexus (ChP) is likely to strongly contribute to this dynamic developmental regulation of CSF composition, but the underlying mechanisms are not understood. Here, we will use a suite of modern tools to test the hypothesis that elevations in calcium concentration in embryonic ChP epithelial cells in response to extrinsic cues is critical for regulating synthesis and secretion of signaling factors into the CSF. Calcium activity regulates transcription and secretion in diverse cells ranging from neurons to salivary gland epithelia. We identified receptors expressed in ChP epithelial cells that mediate calcium entry into the cell, such as the TRPM3 receptor, or that drive calcium release from internal stores, such as the 5HT2C receptor (Htr2c) for serotonin (5- HT, 5-hydroxytryptamine). Our preliminary data suggest that 5-HT regulates embryonic ChP calcium activity, transcription, and vesicle release, and that intact signaling via the 5HT2C receptor in ChP is essential for normal cerebral cortical development. Further, maternal delivery of a selective agonist for the 5HT2C receptor triggers rapid, robust immediate early gene expression in embryonic ChP. Thus, we propose that ChP calcium activity triggered by signals that activate the 5HT2C receptor (and other receptors such as TRPM3) regulates ChP transcription and secretion of signaling factors into the CSF and controls body-brain and maternal-fetal interactions, thereby tightly orchestrating cerebral cortical development. To test this, we will first investigate the effects of 5HT2C and TRPM3 receptor activation by direct application of ligand to the apical surface of epithelial cells during calcium imaging in ChP explants (Aim 1a) and by stimulation of the basal surface following intraperitoneal (IP) delivery of ligands to the maternal dam during in vivo two- photon calcium imaging of attached embryos (Aim 1b). We then assess the transcriptomic impact of such stimulation (Aim 1c), and test whether embryonic ChP calcium activity via activation of 5HT2C receptors and other receptors triggers vesicle release and protein secretion in vitro (Aim 2a) and in vivo (Aim 2b). We will also analyze the effects of disruption of ChP receptor signaling on cortical development (Aim 3a). Disrupted CSF volume, composition, and ventricle formation are common to many neurological conditions. Perturbations in maternal-fetal health can disrupt brain development, in part via dysregulation of serotonergic and other signaling pathways. Our findings provide a novel platform for elucidating the mechanisms underlying dysregulation of brain development by environmental perturbations, thereby providing a conceptual and technical roadmap for future studies on how activity in ChP epithelial cells influences gene expression and protein secretion, with consequences for many neurodevelopmental diseases.

项目摘要/摘要

项目成果

Cerebrospinal Fluid Magnetic Resonance Imaging: Improving Early Diagnosis of Autism and Other Neurodevelopmental Conditions.

脑脊液磁共振成像：改善自闭症和其他神经发育疾病的早期诊断。

• DOI: 10.1016/j.bpsc.2020.05.007
• 发表时间: 2020
• 期刊: Biological psychiatry. Cognitive neuroscience and neuroimaging
• 作者: Xu,Huixin;Lehtinen,MariaK
• 通讯作者: Lehtinen,MariaK

Development and functions of the choroid plexus-cerebrospinal fluid system.

• DOI: 10.1038/nrn3921
• 发表时间: 2015-08
• 期刊: Nature reviews. Neuroscience
• 作者: Lun MP;Monuki ES;Lehtinen MK
• 通讯作者: Lehtinen MK

Progressive Differentiation and Instructive Capacities of Amniotic Fluid and Cerebrospinal Fluid Proteomes following Neural Tube Closure.

• DOI: 10.1016/j.devcel.2015.11.015
• 发表时间: 2015-12-21
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Chau KF;Springel MW;Broadbelt KG;Park HY;Topal S;Lun MP;Mullan H;Maynard T;Steen H;LaMantia AS;Lehtinen MK
• 通讯作者: Lehtinen MK

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.

• DOI: 10.1038/s41418-022-00950-z
• 发表时间: 2022-08
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Li Q;Han Z;Singh N;Terré B;Fame RM;Arif U;Page TD;Zahran T;Abdeltawab A;Huang Y;Cao P;Wang J;Lu H;Lidov HGW;Surendran K;Wu L;Virga JQ;Zhao YT;Schüller U;Wechsler-Reya RJ;Lehtinen MK;Roy S;Liu Z;Stracker TH;Zhao H
• 通讯作者: Zhao H

Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

抗体扩大了血管紧张素受体药理学的范围。

• DOI: 10.1101/2023.08.23.554128
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Skiba,MeredithA;Sterling,SarahM;Rawson,Shaun;Gilman,MorganSA;Xu,Huixin;Nemeth,GenevieveR;Hurley,JosephD;Shen,Pengxiang;Staus,DeanP;Kim,Jihee;McMahon,Conor;Lehtinen,MariaK;Wingler,LauraM;Kruse,AndrewC
• 通讯作者: Kruse,AndrewC