TY - JOUR
T1 - Platelet-activating factor acetylhydrolase expression and activity suggest a link between neuronal migration and platelet-activating factor
AU - Albrecht, Urs
AU - Abu-Issa, Radwan
AU - Rätz, Beate
AU - Hattori, Mitsuharu
AU - Aoki, Junken
AU - Arai, Hiroyuki
AU - Inoue, Keizo
AU - Eichele, Gregor
N1 - Funding Information:
We thank Drs. J. W. Swann and G. D. Clark for critical reading of the manuscript; Drs. H. F. Gilbert and T. Wensel for valuable discussion; Dr. P. Zhang for the GAPDH probe; I. Subramanian, C. Wong, and E. Swindell for technical assistance; and Dr. S. Wakil for allowing us to use his tissue culture facility. U.A. is supported by a fellowship from the Swiss National Science Foundation (823A-042999).
PY - 1996/12/15
Y1 - 1996/12/15
N2 - A hemizygous deletion of LIS1, the gene encoding α(Lis1) protein, causes Miller-Dieker syndrome (MDS). MDS is a developmental disorder characterized by neuronal migration defects resulting in a disorganization of the cerebral and cerebellar cortices. α(Lis1) binds to two other proteins (β and γ) to form a heterotrimeric cytosolic enzyme which hydrolyzes platelet-activating factor (PAF). The existence of heterotrimers is implicated from copurification and crosslinking studies carried out in vitro. To determine whether such a heterotrimeric complex could be present in tissues, we have investigated whether the α(Lis1), β, and γ genes are coexpressed in the developing and adult brain. We have isolated murine cDNAs and show by in situ hybridization that in developing brain tissues α(Lis1), β, and γ genes are coexpressed. This suggests that α(Lis1), β, and γ gene products form heterotrimers in developing neuronal tissues. In the adult brain, α(Lis1) and β mRNAs continue to be coexpressed at high levels while γ gene expression is greatly diminished. This reduction in γ transcript levels is likely to result in a decline of the cellular concentration of α(Lis1), β, and γ heterotrimers. The developmental expression pattern of α(Lis1), β, and γ genes is consistent with the neuronal migration defects seen in MDS; regions containing migrating neurons such as the developing cerebral and cerebellar cortices express these genes at a particularly high level. Furthermore, we uncovered a correlation between γ gene expression, granule cell migration, and PAF hydrolytic activity in the cerebellum. In this tissue γ gene expression and PAF hydrolysis peaked at Postnatal Days P5 and P15, a period during which neuronal migration in the cerebellum is most extensive. Mechanisms by which PAF could affect neuronal migration are discussed.
AB - A hemizygous deletion of LIS1, the gene encoding α(Lis1) protein, causes Miller-Dieker syndrome (MDS). MDS is a developmental disorder characterized by neuronal migration defects resulting in a disorganization of the cerebral and cerebellar cortices. α(Lis1) binds to two other proteins (β and γ) to form a heterotrimeric cytosolic enzyme which hydrolyzes platelet-activating factor (PAF). The existence of heterotrimers is implicated from copurification and crosslinking studies carried out in vitro. To determine whether such a heterotrimeric complex could be present in tissues, we have investigated whether the α(Lis1), β, and γ genes are coexpressed in the developing and adult brain. We have isolated murine cDNAs and show by in situ hybridization that in developing brain tissues α(Lis1), β, and γ genes are coexpressed. This suggests that α(Lis1), β, and γ gene products form heterotrimers in developing neuronal tissues. In the adult brain, α(Lis1) and β mRNAs continue to be coexpressed at high levels while γ gene expression is greatly diminished. This reduction in γ transcript levels is likely to result in a decline of the cellular concentration of α(Lis1), β, and γ heterotrimers. The developmental expression pattern of α(Lis1), β, and γ genes is consistent with the neuronal migration defects seen in MDS; regions containing migrating neurons such as the developing cerebral and cerebellar cortices express these genes at a particularly high level. Furthermore, we uncovered a correlation between γ gene expression, granule cell migration, and PAF hydrolytic activity in the cerebellum. In this tissue γ gene expression and PAF hydrolysis peaked at Postnatal Days P5 and P15, a period during which neuronal migration in the cerebellum is most extensive. Mechanisms by which PAF could affect neuronal migration are discussed.
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U2 - 10.1006/dbio.1996.0330
DO - 10.1006/dbio.1996.0330
M3 - Article
C2 - 8954729
AN - SCOPUS:0030589601
VL - 180
SP - 579
EP - 593
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 2
ER -