Lack of MeCP2 leads to region-specific increase of doublecortin in the olfactory system
Tóm tắt
The protein doublecortin is mainly expressed in migrating neuroblasts and immature neurons. The X-linked gene MECP2, associated to several neurodevelopmental disorders such as Rett syndrome, encodes the protein methyl-CpG-binding protein 2 (MeCP2), a regulatory protein that has been implicated in neuronal maturation and refinement of olfactory circuits. Here, we explored doublecortin immunoreactivity in the brain of young adult female Mecp2-heterozygous and male Mecp2-null mice and their wild-type littermates. The distribution of doublecortin-immunoreactive somata in neurogenic brain regions was consistent with previous reports in rodents, and no qualitative differences were found between genotypes or sexes. Quantitatively, we found a significant increase in doublecortin cell density in the piriform cortex of Mecp2-null males as compared to WT littermates. A similar increase was seen in a newly identified population of doublecortin cells in the olfactory tubercle. In these olfactory structures, however, the percentage of doublecortin immature neurons that also expressed NeuN was not different between genotypes. By contrast, we found no significant differences between genotypes in doublecortin immunoreactivity in the olfactory bulbs. Nonetheless, in the periglomerular layer of Mecp2-null males, we observed a specific decrease of immature neurons co-expressing doublecortin and NeuN. Overall, no differences were evident between Mecp2-heterozygous and WT females. In addition, no differences could be detected between genotypes in the density of doublecortin-immunoreactive cells in the hippocampus or striatum of either males or females. Our results suggest that MeCP2 is involved in neuronal maturation in a region-dependent manner.
Tài liệu tham khảo
Amir RE, Van den Veyver IB, Wan M et al (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet 23:185–188. https://doi.org/10.1038/13810
Bloch J, Kaeser M, Sadeghi Y et al (2011) Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. J Comp Neurol. https://doi.org/10.1002/cne.22547
Braun S, Kottwitz D, Nuber UA (2012) Pharmacological interference with the glucocorticoid system influences symptoms and lifespan in a mouse model of Rett syndrome. Hum Mol Genet 21:1673–1680. https://doi.org/10.1093/hmg/ddr602
Cai Y, Xiong K, Chu Y et al (2009) Doublecortin expression in adult cat and primate cerebral cortex relates to immature neurons that develop into GABAergic subgroups. Exp Neurol. https://doi.org/10.1016/j.expneurol.2008.12.008
Cassel S, Revel MO, Kelche C, Zwiller J (2004) Expression of the methyl-CpG-binding protein MeCP2 in rat brain. An ontogenetic study. Neurobiol Dis 15:206–211. https://doi.org/10.1016/j.nbd.2003.10.011
Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331. https://doi.org/10.1038/85906
Chen Z, Li X, Zhou J et al (2017) Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome. Sci Rep 7:41701. https://doi.org/10.1038/srep41701
Cohen DRS, Matarazzo V, Palmer AM et al (2003) Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis. Mol Cell Neurosci 22:417–429. https://doi.org/10.1016/S1044-7431(03)00026-5
De Marchis S, Fasolo A, Puche AC (2004) Subventricular zone-derived neuronal progenitors migrate into the subcortical forebrain to postnatal mice. J Comp Neurol 476:290–300. https://doi.org/10.1002/cne.20217
Francis F, Koulakoff A, Boucher D et al (1999) Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23:247–256. https://doi.org/10.1016/S0896-6273(00)80777-1
Gleeson JG, Allen KM, Fox JW et al (1998) doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92:63–72. https://doi.org/10.1016/S0092-8674(00)80899-5
Gómez-Climent M, Castillo-Gómez E, Varea E et al (2008) A population of prenatally generated cells in the rat paleocortex maintains an immature neuronal phenotype into adulthood. Cereb Cortex 18:2229–2240. https://doi.org/10.1093/cercor/bhm255
Gómez-Climent Á, Hernández-González S, Shionoya K et al (2011) Olfactory bulbectomy, but not odor conditioned aversion, induces the differentiation of immature neurons in the adult rat piriform cortex. Neuroscience. https://doi.org/10.1016/j.neuroscience.2011.03.004
Gonzales ML, LaSalle JM (2010) The role of MeCP2 in brain development and neurodevelopmental disorders. Curr Psychiatry Rep 12:127–134
Guillemot F, Molnár Z, Tarabykin V, Stoykova A (2006) Molecular mechanisms of cortical differentiation. Eur J Neurosci
Guy J, Hendrich B, Holmes M et al (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326. https://doi.org/10.1038/85899
Hagberg B (2002) Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev 8:61–65. https://doi.org/10.1002/mrdd.10020
Hagg T (2005) Molecular regulation of adult CNS neurogenesis: an integrated view. Trends Neurosci
Kishi N, Macklis JD (2004) MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 27:306–321. https://doi.org/10.1016/j.mcn.2004.07.006
König R, Benedetti B, Rotheneichner P et al (2016) Distribution and fate of DCX/PSA-NCAM expressing cells in the adult mammalian cortex: a local reservoir for adult cortical neuroplasticity? Front Biol 11:193–213 (Beijing)
Li H, Zhong X, Chau KF et al (2014) Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signalling pathway. Nat Commun 5:5601. https://doi.org/10.1038/ncomms6601
Liu YWJ, Curtis MA, Gibbons HM et al (2008) Doublecortin expression in the normal and epileptic adult human brain. Eur J Neurosci. https://doi.org/10.1111/j.1460-9568.2008.06518.x
Lombardi LM, Baker SA, Zoghbi HY (2015) MECP2 disorders: From the clinic to mice and back. J Clin Invest 125:2914–2923
Luzzati F, Bonfanti L, Fasolo A, Peretto P (2009) DCX and PSA-NCAM Expression identifies a population of neurons preferentially distributed in associative areas of different pallial derivatives and vertebrate species. Cereb Cortex. https://doi.org/10.1093/cercor/bhn145
Matarazzo V, Cohen D, Palmer AM et al (2004) The transcriptional repressor Mecp2 regulates terminal neuronal differentiation. Mol Cell Neurosci 27:44–58. https://doi.org/10.1016/j.mcn.2004.05.005
McGill BE, Bundle SF, Yaylaoglu MB et al (2006) Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.0608702103
Moretti P, Bouwknecht JA, Teague R et al (2004) Abnormalities of social interactions and home cage behavior in a mouse model of Rett syndrome. Hum Mol Genet
Mullaney BC, Johnston MV, Blue ME (2004) Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain. Neuroscience 123:939–949. https://doi.org/10.1016/j.neuroscience.2003.11.025
Nacher J, Crespo C, McEwen BS (2002) Doublecortin expression in the adult rat telencephalon. Eur J Neurosci 14:629–644. https://doi.org/10.1046/j.0953-816X.2001.01683.x
Nacher J, Pham K, Gil-Fernandez V, Mcewen BS (2004) Chronic restraint stress and chronic corticosterone treatment modulate differentially the expression of molecules related to structural plasticity in the adult rat piriform cortex. Neuroscience. https://doi.org/10.1016/j.neuroscience.2004.03.038
Nan X, Meehan RR, Bird A (1993) Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res 21:4886–4892. https://doi.org/10.1093/nar/21.21.4886
Nan X, Campoy FJ, Bird A (1997) MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88:471–481. https://doi.org/10.1016/S0092-8674(00)81887-5
Paxinos G, Franklin K (2012) Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates. In: Acad. Press. https://www.elsevier.com/books/paxinos-and-franklins-the-mouse-brain-in-stereotaxic-coordinates/paxinos/978-0-12-391057-8
Ronnett GV, Leopold D, Cai X et al (2003) Olfactory biopsies demonstrate a defect in neuronal development in Rett’s syndrome. Ann Neurol 54:206–218. https://doi.org/10.1002/ana.10633
Rotheneichner P, Belles M, Benedetti B et al (2018) Cellular plasticity in the adult murine piriform cortex: continuous maturation of dormant precursors into excitatory neurons. Cereb Cortex. https://doi.org/10.1093/cercor/bhy087
Rozenkrantz L, Zachor D, Heller I et al (2015) A mechanistic link between olfaction and autism spectrum disorder. Curr Biol 25:1904–1910. https://doi.org/10.1016/j.cub.2015.05.048
Rubio A, Belles M, Belenguer G et al (2016) Characterization and isolation of immature neurons of the adult mouse piriform cortex. Dev Neurobiol 76:748–763. https://doi.org/10.1002/dneu.22357
Saaltink D-J, Håvik B, Verissimo CS et al (2012) Doublecortin and doublecortin-like are expressed in overlapping and non-overlapping neuronal cell population: implications for neurogenesis. J Comp Neurol 520:2805–2823. https://doi.org/10.1002/cne.23144
Samaco RC, Mcgraw CM, Ward CS et al (2013) Female Mecp2+/− mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum Mol Genet 22:96–109. https://doi.org/10.1093/hmg/dds406
Santos M, Temudo T, Kay T et al (2009) Mutations in the MECP2 gene are not a major cause of Rett syndrome-like or related neurodevelopmental phenotype in male patients. J Child Neurol 24:49–55
Santos M, Summavielle T, Teixeira-Castro A et al (2010) Monoamine deficits in the brain of methyl-CpG binding protein 2 null mice suggest the involvement of the cerebral cortex in early stages of Rett syndrome. Neuroscience. https://doi.org/10.1016/j.neuroscience.2010.07.010
Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY (2002) Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet 11:115–124. https://doi.org/10.1093/hmg/11.2.115
Smith ES, Smith DR, Eyring C et al (2018) Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome. Neurobiol Learn Mem Epub ahead. https://doi.org/10.1016/j.nlm.2018.11.007
Smrt RD, Eaves-Egenes J, Barkho BZ et al (2007) Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis 27:77–89. https://doi.org/10.1016/j.nbd.2007.04.005
Squillaro T, Alessio N, Cipollaro M et al (2012) Reduced expression of MECP2 affects cell commitment and maintenance in neurons by triggering senescence: new perspective for Rett syndrome. Mol Biol Cell 23:1435–1445. https://doi.org/10.1091/mbc.E11-09-0784
Zhang X-M, Cai Y, Chu Y et al (2009) Doublecortin-expressing cells persist in the associative cerebral cortex and amygdala in aged nonhuman primates. Front Neuroanat. https://doi.org/10.3389/neuro.05.017.2009