Defects DuringMecp2Null Embryonic Cortex Development Precede the Onset of Overt Neurological Symptoms

Abstract

MeCP2 is associated with several neurological disorders; of which, Rett syndrome undoubtedly represents the most frequent. Its molecular roles, however, are still unclear, and data from animal models often describe adult, symptomatic stages, while MeCP2 functions during embryonic development remain elusive. We describe the pattern and timing of Mecp2 expression in the embryonic neocortex highlighting its low but consistent expression in virtually all cells and show the unexpected occurrence of transcriptional defects in the Mecp2 null samples at a stage largely preceding the onset of overt symptoms. Through the deregulated expression of ionic channels and glutamatergic receptors, the lack of Mecp2 during early neuronal maturation leads to the reduction in the neuronal responsiveness to stimuli. We suggest that such features concur to morphological alterations that begin affecting Mecp2 null neurons around the perinatal age and become evident later in adulthood. We indicate MeCP2 as a key modulator of the transcriptional mechanisms regulating cerebral cortex development. Neurological phenotypes of MECP2 patients could thus be the cumulative result of different adverse events that are already present at stages when no obvious signs of the pathology are evident and are worsened by later impairments affecting the central nervous system during maturation and maintenance of its functionality.

mGlu 7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

“…We detected a significant decrease in Gad2 expression but no change in Grm4 expression (fig. S2, A and B) (28). Furthermore, we probed cortical and hippocampal synaptosome blots for vGlut2 and found no change in expression, thereby suggesting that a nonspecific decrease in presynaptic structures is likely not the cause of mGlu 7 reduction (Fig.…”

CDKL5 localizes at the centrosome and midbody and is required for faithful cell division

“…Neurospheres were prepared as previously described 37 . Briefly, E15.5 embryos were individually dissected in PBS and the neocortex was transferred in Dulbecco’s Modified Eagle Medium/F12 (DMEM) and dissociated by extensive enzymatic digestion with Papaine (Sigma-Aldrich).…”

Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects

“…Indeed, besides the well-known pathological traits - intellectual disability and delayed development - caused by MeCP2 duplication (Ramocki et al, 2010) or MeCP2 loss of function (Chahrour and Zoghbi, 2007), even mild differences in MeCP2 expression turned out to profoundly impact human behavior and brain function (Tantra et al, 2014). To investigate whether the morphological and functional defects observed in the IL-1R8 KO neurons could directly result from increased MeCP2 levels, we silenced MeCP2 in neuronal cultures from IL-1R8 KO mice through the use of a well characterized shRNA construct (Sh MeCP, kind gift of Dr. M. Greenberg, Harvard Medical School), which has been widely used in literature to reduce MeCP2 expression (Zhou et al, 2006; Blackman et al, 2012; Gangisetty et al, 2014; Kishi et al, 2016; Bedogni et al, 2016). DIV 12 neurons were transfected with shCTRL or shMeCP2, and examined for their ability to undergo LTP four days later.…”