The Role of Gremlin2 in Hippocampal Neurogenesis and Neurological Disorders

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. Additionally, when chemically challenged with Kainic Acid (KA), Grem2-/- mice displayed a higher susceptibility to and increased severity of seizures compared to WTs. Despite the role of the hippocampus in learning and memory, Grem2-/- mice did not display evidence of cognitive deficits including no evidence of increase cognitive decline with age. Grem2 also plays a role in fecundity and sex-differentiation, with having sex specific effects on stress resilience and social dominance. Together, our data indicate that Grem2 is vital in maintaining homeostasis of adult hippocampal neurogenesis and structure, and have sex-specific behavioral effects. Furthermore, lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.