Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232.
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
eNeuro. 2024 Oct 17;11(10). doi: 10.1523/ENEURO.0213-23.2024. Print 2024 Oct.
The Bone Morphogenetic Protein (BMP) signaling pathway is vital in neural progenitor cell proliferation, specification, and differentiation. The BMP signaling antagonist Gremlin 2 (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 ( ). Histological analysis of brain sections revealed significant scattering of CA3 pyramidal cells within the dentate hilus in the hippocampus of mice. Furthermore, the number of proliferating neural stem cells and neuroblasts was significantly decreased in the subgranular zone of mice compared with that of wild-type (WT) controls. Due to the role of hippocampal neurogenesis in neurological disorders, we tested mice on a battery of neurobehavioral tests. mice exhibited increased anxiety on the elevated zero maze in response to acute and chronic stress. Specifically, male mice showed increased anxiogenesis following chronic stress, and this was correlated with higher levels of BMP signaling and decreased proliferation in the dentate gyrus. Additionally, when chemically challenged with kainic acid, mice displayed a higher susceptibility to and increased severity of seizures compared with WTs. Together, our data indicate that Grem2 regulates BMP signaling and is vital in maintaining homeostasis in adult hippocampal neurogenesis and structure. Furthermore, the lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.
骨形态发生蛋白（BMP）信号通路对神经祖细胞的增殖、特化和分化至关重要。BMP 信号拮抗剂 Gremlin 2（Grem2）是成年脑中表达的最有效的天然 BMP 抑制剂；然而，其功能仍然未知。为了解决这一知识空白，我们通过同源重组（）分析了缺乏 Grem2 的小鼠。对脑切片的组织学分析显示，在海马 CA3 锥体神经元内， 小鼠的齿状回门区的锥体神经元明显分散。此外，与野生型（WT）对照组相比， 小鼠的齿状回颗粒下区增殖的神经干细胞和神经母细胞数量显著减少。由于海马神经发生在神经紊乱中的作用，我们在一系列神经行为测试中对小鼠进行了测试。 小鼠在急性和慢性应激时在高架零迷宫上表现出焦虑增加。具体而言，雄性 小鼠在慢性应激后出现焦虑增加，这与 BMP 信号升高和齿状回增殖减少有关。此外，当用海人酸化学挑战时， 小鼠与 WT 相比，表现出更高的易感性和更严重的癫痫发作。总之，我们的数据表明 Grem2 调节 BMP 信号，对于维持成年海马神经发生和结构的内稳态至关重要。此外，缺乏 Grem2 导致与神经发生相关的疾病（如焦虑和癫痫）的发展和进展。
