Early Dendritic Morphogenesis of Adult-Born Dentate Granule Cells Is Regulated by FHL2

Abstract

Dentate granule cells (DGCs), the progeny of neural stem cells (NSCs) in the subgranular zone of the dentate gyrus (DG), must develop and functionally integrate with the mature cohort of neurons in order to maintain critical hippocampal functions throughout adulthood. Dysregulation in the continuum of DGC development can result in aberrant morphology and disrupted functional maturation, impairing neuroplasticity of the network. Yet, the molecular underpinnings of the signaling involved in adult-born DGC maturation including dendritic growth, which correlates with functional integration, remains incompletely understood. Given the high metabolic activity in the dentate gyrus (DG) required to achieve continuous neurogenesis, we investigated the potential regulatory role of a cellular metabolism-linked gene recently implicated in NSC cycling and neuroblast migration, called Four and a half LIM domain 2 (FHL2). The FHL2 protein modulates numerous pathways related to proliferation, migration, survival and cytoskeletal rearrangement in peripheral tissues, interacting with the machinery of the sphingosine-1-phosphate pathway, also known to be highly active especially in the hippocampus. Yet, the potential relevance of FHL2 to adult-born DGC development remains unknown. To elucidate the role of FHL2 in DGC development in the adult brain, we first confirmed the endogenous expression of FHL2 in NSCs and new granule cells within the DG, then engineered viral vectors for genetic manipulation experiments, investigating morphological changes in early stages of DGC development. Overexpression of FHL2 during early DGC development resulted in marked sprouting and branching of dendrites, while silencing of FHL2 increased dendritic length. Together, these findings suggest a novel role of FHL2 in adult-born DGC morphological maturation, which may open up a new line of investigation regarding the relevance of this gene in physiology and pathologies of the hippocampus such as mesial temporal lobe epilepsy (MTLE).

Multipronged Attack of Stem Cell Therapy in Treating the Neurological and Neuropsychiatric Symptoms of Epilepsy

“…As numerous studies indicate, epilepsy’s pathology is intricate and encompasses a wide-range of mechanisms, several of which may serve as therapeutic targets for stem-cell based remedies. Indeed, irregular neuronal pathways, potentially engendered by the dysregulated construction of the neuronal network, has been associated with epilepsy ( Homan et al, 2018 ; Schuster et al, 2019 ; Ahamad et al, 2020 ). Impaired dentate granule cell (DGC) development from NSCs may spur warped hippocampal activity, neuroplasticity, and formation of mature neurons, which would lead to hippocampal-related disorders like mesial temporal lobe epilepsy (MTLE) ( Ahamad et al, 2020 ).…”

“…Indeed, irregular neuronal pathways, potentially engendered by the dysregulated construction of the neuronal network, has been associated with epilepsy ( Homan et al, 2018 ; Schuster et al, 2019 ; Ahamad et al, 2020 ). Impaired dentate granule cell (DGC) development from NSCs may spur warped hippocampal activity, neuroplasticity, and formation of mature neurons, which would lead to hippocampal-related disorders like mesial temporal lobe epilepsy (MTLE) ( Ahamad et al, 2020 ). It has been indicated that FHL2 protein is involved with dentate gyrus metabolism and neurogenesis ( Ahamad et al, 2020 ).…”

“…Impaired dentate granule cell (DGC) development from NSCs may spur warped hippocampal activity, neuroplasticity, and formation of mature neurons, which would lead to hippocampal-related disorders like mesial temporal lobe epilepsy (MTLE) ( Ahamad et al, 2020 ). It has been indicated that FHL2 protein is involved with dentate gyrus metabolism and neurogenesis ( Ahamad et al, 2020 ). Findings suggested that FHL2 overexpression in DGCs induce heightened dendritic sprouting; whereas, FHL2 repression bolsters the length of dendrites ( Ahamad et al, 2020 ).…”

“…It has been indicated that FHL2 protein is involved with dentate gyrus metabolism and neurogenesis ( Ahamad et al, 2020 ). Findings suggested that FHL2 overexpression in DGCs induce heightened dendritic sprouting; whereas, FHL2 repression bolsters the length of dendrites ( Ahamad et al, 2020 ). Moreover, understanding the mechanisms behind hippocampal deficits that manifest in MTLE is key to formulating cell-based therapeutic strategies to mitigate these impairments.…”