Abstract
Dentate granule cells (DGCs), the progeny of neural stem cells (NSCs) in the sub-granular 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).
Highlights
The discovery of mammalian adult hippocampal neurogenesis has been fundamental to our understanding of physiological homeostasis in the adult brain (Altman and Das, 1965)
In order to study the regulatory role of FHL2 in the adult brain, we first mapped the expression of FHL2 in the subfields of the adult hippocampus [dentate gyrus (DG), CA3, CA2, and CA1] (Figures 1A–D)
We found that manipulation of FHL2 disrupts dendritic modeling in newborn Dentate granule cells (DGCs) in the hippocampus by causing dendritic hypertrophy, a phenotypic recapitulation of neurons of patients with mesial temporal lobe epilepsy (MTLE) which points to a potential underlying mechanism (Ryufuku et al, 2011)
Summary
The discovery of mammalian adult hippocampal neurogenesis has been fundamental to our understanding of physiological homeostasis in the adult brain (Altman and Das, 1965). Studies of cellular metabolism and pharmacology have shown that lipid metabolism and signaling play an active role in adult neural stem cell cycling and are important for synaptic homeostasis and functional regulation of newborn neurons (Kanno and Nishizaki, 2011; Riganti et al, 2016; Beckervordersandforth et al, 2017; Stessin et al, 2017; Callihan et al, 2018). In cell culture S1P triggers RhoA GTPase activation followed by nuclear translocation of FHL2, where it acts as a transcriptional co-regulator for a number of genes including those involved in molecular memory and extracellular communication (Muller et al, 2002). One recent study identified an alternative action of FHL2 expressed in adult neural stem cells (NSCs) that may help explain its clinical phenotype and physiological importance in the brain. Kim et al reported that global FHL2 deletion in mice via transgenic constitutive knockout led to low self-renewal activity among NSCs, premature differentiation into astrocytes at the expense of neuronal differentiation and delayed neuroblast migration in the developing brain (Kim et al, 2019)
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