Downregulation of Sphingosine 1-Phosphate Receptor 1 Promotes the Switch from Tangential to Radial Migration in the OB

Abstract

Neuroblast migration is a highly orchestrated process that ensures the proper integration of newborn neurons into complex neuronal circuits. In the postnatal rodent brain, neuroblasts migrate long distances from the subependymal zone of the lateral ventricles to the olfactory bulb (OB) within the rostral migratory stream (RMS). They first migrate tangentially in close contact to each other and later radially as single cells until they reach their final destination in the OB. Sphingosine 1-phosphate (S1P) is a bioactive lipid that interacts with cell-surface receptors to exert different cellular responses. Although well studied in other systems and a target for the treatment of multiple sclerosis, little is known about S1P in the postnatal brain. Here, we report that the S1P receptor 1 (S1P1) is expressed in neuroblasts migrating in the RMS. Using in vivo and in vitro gain-and loss-of-function approaches in both wild-type and transgenic mice, we found that the activation of S1P1 by its natural ligand S1P, acting as a paracrine signal, contributes to maintain neuroblasts attached to each other while they migrate in chains within the RMS. Once in the OB, neuroblasts cease to express S1P1, which results in cell detachment and initiation of radial migration, likely via downregulation of NCAM1 and ␤1 integrin. Our results reveal a novel physiological function for S1P1 in the postnatal brain, directing the path followed by newborn neurons in the neurogenic niche.

Timely Inhibitory Circuit Formation Controlled by Abl1 Regulates Innate Olfactory Behaviors in Mouse

“…Abl1 deficiency did not affect the tangential migration of interneurons through the RMS from SVZ into the OB, consistent with a previous report (Qiu et al, 2010). After arrival in the OB via tangential migration, interneurons undergo dynamic structural changes for radial migration and functional integration into preexisting circuits (Alfonso et al, 2015;Whitman and Greer, 2007). First, cellular detachment from the migratory chain toward single cells is mediated by the regulation or modification of celladhesion molecules, such as the neural cell-adhesion molecule, integrins, or sphingosine 1-phosphate, contributing to cytoskeleton arrangement (Valiente and Marín, 2010).…”

Mechanisms of neuronal migration in the adult brain

“…A decrease in sphingosine 1‐phosphate receptor 1, which regulates adhesion between neuroblasts, is also involved in detachment (Alfonso et al . ). Interestingly, olfactory deprivation decreases the expression of Reelin (Okuyama‐Yamamoto et al .…”

“…Signals mediated by sphingosine 1‐phosphate receptor 1, a receptor for the bioactive lipid sphingosine1‐phosphate (Alfonso et al . ), or mediated by the P2Y1 purinergic receptor, which is activated by extracellular ATP (Cao et al . ), are reported to control chain formation by regulating the expression of adhesion proteins in the neuroblasts.…”

“…V-SVZ-derived neuroblasts express the cell-adhesion molecules polysialylated neural cell-adhesion molecule (Hu et al 1996;Chazal et al 2000) and N-cadherin (Yagita et al 2009), and suppressing the expression or function of these molecules disrupts chain formation. Signals mediated by sphingosine 1phosphate receptor 1, a receptor for the bioactive lipid sphingosine1-phosphate (Alfonso et al 2015), or mediated by the P2Y1 purinergic receptor, which is activated by extracellular ATP (Cao et al 2015), are reported to control chain formation by regulating the expression of adhesion proteins in the neuroblasts. b1 and b8 class integrins, which are heterophilic adhesion molecules, are also expressed in V-SVZ-derived neuroblasts.…”

“…Several ECM proteins such as Reelin, Tenascin-R, and Prokineticin-2 control the detachment process (Hack et al 2002;Saghatelyan et al 2004;Ng et al 2005). A decrease in sphingosine 1-phosphate receptor 1, which regulates adhesion between neuroblasts, is also involved in detachment (Alfonso et al 2015). Interestingly, olfactory deprivation decreases the expression of Reelin (Okuyama-Yamamoto et al 2005) and Tenascin-R (Saghatelyan et al 2004) in the olfactory bulb, suggesting that olfactory input prompts neuroblasts to detach from the chain and begin migrating radially.…”