Requirement for the lp _A1 lysophosphatidic acid receptor gene in normal suckling behavior

Abstract

Although extracellular application of lysophosphatidic acid (LPA) has been extensively documented to produce a variety of cellular responses through a family of specific G protein-coupled receptors, the in vivo organismal role of LPA signaling remains largely unknown. The first identified LPA receptor gene, lp A1͞vzg-1͞ edg-2, was previously shown to have remarkably enriched embryonic expression in the cerebral cortex and dorsal olfactory bulb and postnatal expression in myelinating glia including Schwann cells. Here, we show that targeted deletion of lp A1 results in approximately 50% neonatal lethality, impaired suckling in neonatal pups, and loss of LPA responsivity in embryonic cerebral cortical neuroblasts with survivors showing reduced size, craniofacial dysmorphism, and increased apoptosis in sciatic nerve Schwann cells. The suckling defect was responsible for the death among lpA1 (؊/؊) neonates and the stunted growth of survivors. Impaired suckling behavior was attributable to defective olfaction, which is likely related to developmental abnormalities in olfactory bulb and͞or cerebral cortex. Our results provide evidence that endogenous lysophospholipid signaling requires an lp receptor gene and indicate that LPA signaling through the LP A1 receptor is required for normal development of an inborn, neonatal behavior.

Expression patterns of the lysophospholipid receptor genes during mouse early development

“…Although Lpa 1 is predominantly expressed in the early brain primordia, Lpa 1 -null mice exhibit no obvious abnormalities in brain formation, except for sporadic reductions in cerebral wall thickness (Contos et al, 2000; reviewed by Choi et al, 2008). However, as null mutants for autotaxin, an enzyme required for LPA biosynthesis, exhibit severe defects in neural tube formation (Tanaka et al, 2006;van Meeteren et al, 2006), there is no doubt that LPA signaling is required for early brain development.…”

“…Lpa 1 -null mice exhibit abnormalities in craniofacial structures that are known to be derived from neural crest cells (Contos et al, 2000;Harrison et al, 2003). It is thus conceivable that LPA 1 -mediated signaling plays a role in the development of this and other neural crest-derived structures.…”

“…Mice deficient in each of the LPA or S1P receptor genes (excluding Lpa 4 , Lpa 5 , and S1p 4 ) have been reported, and double-or triple-knockout mice have been produced for Lpa 1-3 and S1p 1-3 (Contos et al, 2000Kingsbury et al, 2003;Ye et al, 2005Ye et al, , 2008Liu et al, 2000;MacLennan et al, 2001MacLennan et al, , 2006Kono et al, 2004Kono et al, , 2007Cinamon et al, 2004;Jaillard et al, 2005;Herr et al, 2007;Means et al, 2007). However, none of the genetically modified mice reported so far appear to exhibit apparent deficiencies in the formation of somites, possibly because of functional compensation or redundancy among LPA/S1P receptor genes.…”

“…Targeted mutation of these receptor genes in mice has begun to provide indications of their in vivo roles. For example, homozygotes for targeted null mutations of S1p 1 exhibit vascular defects (Liu et al, 2000), as well as impaired chondrocyte condensation and digit morphogenesis (Chae et al, 2004); S1p 2 -null mice exhibit postnatal auditory and vestibular dysfunction (MacLennan et al, 2006;Herr et al, 2007;Kono et al, 2007); Lpa 1 -null mice develop craniofacial abnormalities and a sucking defect (Contos et al, 2000); and targeted deletion of Lpa 3 results in delayed implantation and altered embryo spacing (Ye et al, 2005). In contrast, single mutations in either S1p 3 or Lpa 2 have been reported to display no obvious phenotypic abnormalities, suggesting redundant roles among these lipid receptors (Ishii et al, 2001;.…”

Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid

“…It was recently shown that LPA can induce fetal hydrocephalus in the mouse by an aberrant activation of Lpa 1 on NS/PCs during development ( 19 ). LPA also acts through the Rho pathway to induce morphological rearrangements in neuroblasts and neurons (20)(21)(22)(23)(24), including actin polymerization ( 21 ) that leads to the formation of retraction fi bers, neurite retraction ( 21,(25)(26)(27)(28)(29)(30)(31)(32), cell rounding ( 26,29,33,34 ), cluster compaction (35)(36)(37)(38), and growth cone collapse ( 21,26,27 ).…”