Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice.
Disruptions in brain-derived neurotrophic factor (BDNF) expression are proposed to contribute to the molecular pathogenesis of Rett syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in methyl-CpG-binding protein-2 (MeCP2). Although MeCP2 is a transcriptional regulator of BDNF, it is unknown how MeCP2 mutations affect transsynaptic BDNF signaling. Our findings demonstrate an early, abnormal neurosecretory phenotype in MeCP2-deficient neurons characterized by significant increases in the percentage of cellular BDNF content available for release. However, loss of MeCP2 also results in deficits in total cell BDNF content that are developmentally regulated in a cell-type-specific manner. Thus, the net effect of MeCP2 loss on absolute BDNF secretion changes with age and is determined by both the amount of BDNF available for release and progressive declines in total cellular BDNF. We propose, therefore, that loss of MeCP2 function disrupts transsynaptic BDNF signaling by perturbing the normal balance between BDNF protein levels and secretion. However, mutant neurons are capable of secreting wild-type levels of BDNF in response to high-frequency electrical stimulation. In addition, we found elevated exocytic function in Mecp2(-/y) adrenal chromaffin cells, indicating that the Mecp2 null mutation is associated with alterations of neurosecretion that are not restricted to BDNF. These findings are the first examples of abnormal neuropeptide and catecholamine secretion in a mouse model of RTT.
Wang
Hong
H
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4975, USA.
Chan
Shyue-an
SA
Ogier
Michael
M
Hellard
David
D
Wang
Qifang
Q
Smith
Corey
C
Katz
David M
DM
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D051783:Methyl-CpG-Binding Protein 2