Background Plasticity‐related genes (Prgs/PRGs) or lipid phosphate phosphatase‐related proteins (LPPRs) comprise five known members, which have been linked to neuronal differentiation processes, such as neurite outgrowth, axonal branching, or dendritic spine formation. PRGs are highly brain‐specific and belong to the lipid phosphate phosphatases (LPPs) superfamily, which influence lipid metabolism by dephosphorylation of bioactive lipids. PRGs, however, do not possess enzymatic activity, but modify lipid metabolism in a way that is still under investigation. Results We analyzed mRNA expression levels of all Prgs during mouse brain development, in the hippocampus, neocortex, olfactory bulbs, and cerebellum. We found different spatio‐temporal expression patterns for each of the Prgs, and identified a high expression of the uncharacterized Prg4 throughout brain development. Unlike its close family members PRG3 and PRG5, PRG4 did not induce filopodial outgrowth in non‐neuronal cell lines, and does not localize to the plasma membrane of filopodia. Conclusion We showed PRG4 to be highly expressed in the developing and the adult brain, suggesting that it is of vital importance for normal brain function. Despite its similarities to other family members, it seems not to be involved in changes of cell morphology; instead, it is more likely to be associated with intracellular signaling.

Background LPA is a small bioactive phospholipid that acts as an extracellular signaling molecule and is involved in cellular processes, including cell proliferation, migration, and differentiation. LPA acts by binding and activating at least six known G protein–coupled receptors: LPA 1–6 . In recent years, LPA has been suggested to play an important role both in normal neuronal development and under pathological conditions in the nervous system. Results We show the expression pattern of LPA receptors during mouse brain development by using qRT‐PCR, in situ hybridization, and immunocytochemistry. Only LPA 1 , LPA 2, LPA 4, and LPA 6 mRNA transcripts were detected throughout development stages from embryonic day 16 until postnatal day 30 of hippocampus, neocortex, cerebellum, and bulbus olfactorius in our experiments, while expression of LPA 3 and LPA 5 genes was below detection level. In addition to our qRT‐PCR results, we also analyzed the cellular protein expression of endogenous LPA receptors, with focus on LPA 1 and LPA 2 within postnatal brain slices and primary neuron differentiation with and without cytoskeleton stabilization and destabilization. Conclusions The expression of LPA receptors changes depends on the developmental stage in mouse brain and in cultured hippocampal primary neurons. Interestingly, we found that commercially available antibodies for LPA receptors are largely unspecific.

During adult neurogenesis, neuronal stem cells differentiate into mature neurons that are functionally integrated into the existing network. One hallmark during the late phase of this neurodifferentiation process is the formation of dendritic spines. These morphological specialized structures form the basis of most excitatory synapses in the brain, and are essential for neuronal communication. Additionally, dendritic spines are affected in neurological disorders, such as Alzheimer’s disease or schizophrenia. However, the mechanisms underlying spinogenesis, as well as spine pathologies, are poorly understood. Plasticity-related Gene 5 (PRG5), a neuronal transmembrane protein, has previously been linked to spinogenesis in vitro. Here, we analyze endogenous expression of the PRG5 protein in different mouse brain areas, as well as on a subcellular level. We found that native PRG5 is expressed dendritically, and in high abundance in areas characterized by their regenerative capacity, such as the hippocampus and the olfactory bulb. During adult neurogenesis, PRG5 is specifically expressed in a late phase after neuronal cell-fate determination associated with dendritic spine formation. On a subcellular level, we found PRG5 not to be localized at the postsynaptic density, but at the base of the synapse. In addition, we showed that PRG5-induced formation of membrane protrusions is independent from neuronal activity, supporting a possible role in the morphology and stabilization of spines.

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The functional importance of neuronal differentiation of the transmembrane proteins’ plasticity-related genes 3 (PRG3) and 5 (PRG5) has been shown. Although their sequence is closely related, they promote different morphological changes in neurons. PRG3 was shown to promote neuritogenesis in primary neurons; PRG5 contributes to spine induction in immature neurons and the regulation of spine density and morphology in mature neurons. Both exhibit intracellularly located C-termini of less than 50 amino acids. Varying C-termini suggested that these domains shape neuronal morphology differently. We generated mutant EGFP-fusion proteins in which the C-termini were either swapped between PRG3 and PRG5, deleted, or fused to another family member, plasticity-related gene 4 (PRG4), that was recently shown to be expressed in different brain regions. We subsequently analyzed the influence of overexpression in immature neurons. Our results point to a critical role of the PRG3 and PRG5 C-termini in shaping early neuronal morphology. However, the results suggest that the C-terminus alone might not be sufficient for promoting the morphological effects induced by PRG3 and PRG5.