Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion.
Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here we provide evidence that primary hippocampal neurons from a mouse model of 22q11.2 deletion (Df(16)A(+/-) mice) have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits were prevented by introduction of the enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene in the 22q11.2 locus, and they were also observed in primary cultures from Zdhhc8-deficient mice. Many of these deficits were also present in the hippocampi of adult Df(16)A(+/-) and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
Jun
J
Mukai
Alefiya
A
Dhilla
Liam J
LJ
Drew
Kimberly L
KL
Stark
Luxiang
L
Cao
Amy B
AB
MacDermott
Maria
M
Karayiorgou
Joseph A
JA
Gogos
D000217:Acyltransferases / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D001927:Brain Diseases / Q000473:pathology*; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003712:Dendrites / Q000473:pathology; D049229:Dendritic Spines / Q000473:pathology; D003952:Diagnostic Imaging / Q000379:methods; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D051528:Guanylate Kinases; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000473:pathology / Q000502:physiology; D014162:Transfection / Q000379:methods
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D000217:Acyltransferases; C488097:ZDHHC8 protein, human; D051528:Guanylate Kinases