Yao, Peijia;
Liu, Xueli;
Miao, Qiang;
Li, Changxue;
Zhou, Huaixiang;
Li, Huiliang;
Mao, Xinliang;
... Li, Ningning; + view all
(2024)
Expression mapping of GREM1 and functional contribution of its-secreting-cells in the brain using transgenic mouse models.
Experimental Neurology
, 373
, Article 114649. 10.1016/j.expneurol.2023.114649.
Preview |
Text
1-s2.0-S0014488623003345-main.pdf Download (14MB) | Preview |
Abstract
Gremlin 1 (Grem1) is a secreted protein that antagonizes bone morphogenetic proteins (BMPs). While abnormal Grem1 expression has been reported to cause behavioral defects in postpartum mice, the spatial and cellular distribution of GREM1 in the brain and the influence of the Grem1-secreating cells on brain function and behavior remain unclear. To address this, we designed a genetic cassette incorporating a 3 × Flag-TeV-HA-T2A-tdTomato sequence, resulting in the creation of a novel Grem1Tag mouse model, expressing an epitope tag (3 × Flag-TeV-HA-T2A) followed by a fluorescent reporter (tdTomato) under the control of the endogenous Grem1 promoter. This design facilitated precise tracking of the cell origin and distribution of GREM1 in the brain using tdTomato and Flag (or HA) markers, respectively. We confirmed that the Grem1Tag mouse exhibited normal motor, cognitive, and social behaviors at postnatal 60 days (P60), compared with C57BL/6 J controls. Through immunofluorescence staining, we comprehensively mapped the distribution of Grem1-secreting cells across the central nervous system. Pervasive Grem1 expression was observed in the cerebral cortex (Cx), medulla, pons, and cerebellum, with the highest levels in the Cx region. Notably, within the Cx, GREM1 was predominantly secreted by excitatory neurons, particularly those expressing calcium/calmodulin-dependent protein kinase II alpha (Camk2a), while inhibitory neurons (parvalbumin-positive, PV+) and glial cells (oligodendrocytes, astrocytes, and microglia) showed little or no Grem1 expression. To delineate the functional significance of Grem1-secreting cells, a selective ablation at P42 using a diphtheria toxin A (DTA) system resulted in increased anxiety-like behavior and impaired memory in mice. Altogether, our study harnessing the Grem1Tag mouse model reveals the spatial and cellular localization of GREM1 in the mouse brain, shedding light on the involvement of Grem1-secreting cell in modulating brain function and behavior. Our Grem1Tag mouse serves as a valuable tool for further exploring the precise role of Grem1 in brain development and disease.
Type: | Article |
---|---|
Title: | Expression mapping of GREM1 and functional contribution of its-secreting-cells in the brain using transgenic mouse models |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1016/j.expneurol.2023.114649 |
Publisher version: | http://dx.doi.org/10.1016/j.expneurol.2023.114649 |
Language: | English |
Additional information: | © 2023 The Authors. Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | BMPs, Camk2a, DTA, Distribution, Grem1, Neuron |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
URI: | https://discovery.ucl.ac.uk/id/eprint/10183740 |
Archive Staff Only
View Item |