Synaptic maturation is critical for brain development. Dendritic arborization and spine/synapse formation are regulated in part by localized Ca2+ dynamics. Alterations in synaptic development are a fundamental feature of abnormal brain development in several childhood developmental disorders including Rett syndrome (RTT), Fragile X syndrome, and Down syndrome. Postmortem Rett brains exhibit reduced brain volume and marked reduction of dendritic development, maturation, and branching. Recent findings demonstrate that translation of MeCP2, the transcriptional repressor protein involved in RTT, is suppressed by CREB-dependent transcription of microRNA132 (miR132). Activity-dependent activation of CREB and formation of miR132 is regulated by the CaMKK/CaMKI/MEK/ERK signaling pathway. This pathway has previously been established to play a critical role in the normal development of dendritic arborization and synapse maturation. We propose to investigate the CaMKK/CaMKI signaling pathway as a potential mechanism regulating MeCP2-dependent synaptogenesis in the following specific aims: (1) CaMKI, via regulation of CREB-dependent miR132, maintains appropriate levels of MeCP2 to allow synaptogenesis;(2) alternatively, MeCP2 regulates expression of BDNF, thereby activating CaMKI which is known to modulate actin dynamics and synapse formation via Rac and Pak.
In Aims 1 and 2 we will utilize multiple, independent approaches to map these signaling pathways: phospho-specific antibodies to assess the activation state of signaling components, a variety of pharmacological inhibitors, transfection of dominant-negative and constitutively-active signaling constructs, and RNAi technologies to suppress endogenous proteins. These multiple approaches are necessary since each individually has limitations.
These findings may contribute to the understanding of the pathogenesis of a spectrum of neurodevelopmental and neuropsychiatric disorders that exhibit abnormal spine development. Addressing how CaM kinase signaling pathways are involved in synaptogenesis may therefore provide new avenues for the therapy of RTT and other childhood developmental disorders associated with MeCP2 and abnormal spine development.
| Heng, Mary Y; Lin, Shu-Ting; Verret, Laure et al. (2013) Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J Clin Invest 123:2719-29 |
