Abstract
The Bone Morphogenic Protein (BMP) signaling pathway is vital in neural progenitor cell proliferation, specification, and differentiation. The BMP signaling antagonist Gremlin2 (Grem2) is the most potent natural inhibitor of BMP expressed in the adult brain, however its function remains unknown. To address this knowledge gap, we have analyzed mice lacking Grem2 via homologous recombination (Grem2-/-). Histological analysis of brain sections revealed significant scattering of CA3 pyramidal cells within the dentate hilus in the hippocampus of Grem2-/- mice. Furthermore, the number of proliferating neural stem cells (NSCs) and neuroblasts was significantly decreased in the subgranular zone (SGZ) of Grem2-/- mice compared to wild-type (WT) controls. Due to the role of hippocampal neurogenesis in neurological disorders, we tested mice on a battery of neurobehavioral tests. Grem2-/- mice exhibited increased anxiety on the elevated zero maze (EZM) in response to acute and chronic stress. Specifically, male Grem2-/- mice showed increased anxiogenesis following chronic stress, and this was corelated with higher levels of BMP signaling and decreased proliferation in the dentate gyrus (DG). Additionally, when chemically challenged with Kainic Acid (KA), Grem2-/- mice displayed a higher susceptibility to and increased severity of seizures compared to WTs. Together, our data indicate that Grem2 regulates BMP signaling and is vital in maintaining homeostasis in adult hippocampal neurogenesis and structure. Furthermore, lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.
Significance statement Regulation of adult neurogenesis via BMP signaling is important in various neurological disorders. Grem2 is a secreted protein regulator of BMP signaling with strong inhibitory potential due to its unique formation of daisy chain polymers with BMP ligands. However, despite being highly expressed in the hippocampus, the role of the BMP inhibitor Grem2 in hippocampal structure and function is unknown. This paper provides the first evidence that Grem2 is necessary for proper BMP signaling and hippocampal morphology and neurogenesis. Furthermore, we found increased stress-induced anxiety and seizure susceptibility phenotypes in mice lacking Grem2. Together, our data introduce a novel molecular mechanism of hippocampal homeostasis and putative therapeutic target of neurological disorders.
Footnotes
We would like to thank the Vanderbilt Mouse Neurobehavioral Lab and the director, Dr. Fiona A. Harrison for outstanding assistance and advice on the design and execution of the neurobehavioral tests. We are also thankful to the Vanderbilt Digital Histology Shared Resource for outstanding services. Image analysis and presentation were performed in part through the use of the Vanderbilt Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637 and EY08126).
Authors report no competing financial interests
This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH; R01HL138519) and the Department of Defense (W81XWH-16-1-0622) to AKH, and NIH National Human Genome Research Institute (R35HG010718, R01HG011138) and National Institute on Aging (R56AG068026) to ERG.
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