Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus

Abstract

Neurogenesis persists in certain regions of the adult brain including the subgranular zone of the hippocampal dentate gyrus wherein its regulation is essential, particularly in relation to learning, stress and modulation of mood. Lysophosphatidic acid (LPA) is an extracellular signaling phospholipid with important neural regulatory properties mediated by specific G protein-coupled receptors, LPA1-5. LPA1 is highly expressed in the developing neurogenic ventricular zone wherein it is required for normal embryonic neurogenesis, and, by extension may play a role in adult neurogenesis as well. By means of the analyses of a variant of the original LPA1-null mutant mouse, termed the Malaga variant or “maLPA1-null,” which has recently been reported to have defective neurogenesis within the embryonic cerebral cortex, we report here a role for LPA1 in adult hippocampal neurogenesis. Proliferation, differentiation and survival of newly formed neurons are defective in the absence of LPA1 under normal conditions and following exposure to enriched environment and voluntary exercise. Furthermore, analysis of trophic factors in maLPA1-null mice demonstrated alterations in brain-derived neurotrophic factor and insulin growth factor 1 levels after enrichment and exercise. Morphological analyses of doublecortin positive cells revealed the anomalous prevalence of bipolar cells in the subgranular zone, supporting the operation of LPA1 signaling pathways in normal proliferation, maturation and differentiation of neuronal precursors.

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…and maLPA 1 Ϫ/Ϫ mice also display craniofacial dysmorphism and defects in adult hippocampal neurogenesis, traits that are associated with autism (112). These data strongly implicate LPA and LPA 1 receptor signaling in neurodevelopmental and neuropsychiatric disorders.…”

“…Neurodevelopment defects in maLPA 1 include reduced NPC proliferation, increased cerebral cortical apoptosis, decreased cortical size, and premature expression of neuronal markers (93). Defects in the proliferation, differentiation, and survival of new neurons were also impacted during adult hippocampal neurogenesis (112). Additionally, maLPA 1 mice showed several behavioral defi cits, including inhibition of fear extinction (113) and aggravation of chronic stressinduced impairment to hippocampal neurogenesis (114).…”

Stress coping stimulates hippocampal neurogenesis in adult monkeys

“…The fifth gene encodes PRG-3, a new member of the brain-specific family of lysophospholipidmodifying proteins (LLPs) (48). Down-regulation of LLPs increases lysophosphatidic acid signaling (48), which, in turn, promotes hippocampal neurogenesis in adult mice (49).…”

Autotaxin/Lpar3 signaling regulates Kupffer's vesicle formation and left-right asymmetry in zebrafish

“…These signals are then translated into altered gene transcription (Stortelers et al, 2008) and a wide range of cellular responses, including stimulation of cell proliferation, migration and survival as well as cytoskeletal reorganization and morphological changes (Fukushima et al, 1998;Moolenaar et al, 2004;Choi et al, 2010). In mice, Atx and LPA signaling are critically involved in vascular development van Meeteren et al, 2006b), nervous system function Yuan et al, 2003;Matas-Rico et al, 2008), lymphocyte homing (Kanda et al, 2008) and tumor progression (Mills and Moolenaar, 2003;Houben and Moolenaar, 2011). Knockout of the genes encoding the three major and closely related LPA receptors (Lpar1-3) in mice resulted in relatively mild phenotypes (Choi et al, 2008).…”

“…Lpar1 -/-mice show perinatal lethality due to defective suckling (Contos et al, 2000). In addition, defects in neural development have also been observed (Matas-Rico et al, 2008).…”