Editors' ChoiceNeuroscience

Misbehaving without MeCP2

Sci. Signal.  08 Nov 2016:
Vol. 9, Issue 453, pp. ec262
DOI: 10.1126/scisignal.aal3437

Mutations that affect the function of the transcriptional regulator MeCP2 or its interaction with specific binding partners cause the neurological disorder Rett syndrome. Rett syndrome is characterized by repetitive hand movements, impaired motor and cognitive function, and autistic-like behaviors. A pair of papers examines the role of MeCP2 and its interaction with different families of histone deacetylases (HDACs) in different areas of the brain. Nott et al. found that mice with conditional knockout of Hdac3 in excitatory neurons of the forebrain (hippocampus and cortex, not striatum) had altered locomotor activity, abnormal exploratory behavior, social and cognitive deficits, impaired memory, and exhibited hind limb clasping (a rodent correlate of the repetitive hand movement behavior observed in Rett syndrome patients). Transcription and promoter analysis of control, Hdac3 knockout, and Mecp2 knockout mouse hippocampi showed that HDAC3 was recruited to active genes by MeCP2 and that these genes were enriched for binding motifs for the FOXO family of transcription factors. Hdac3 knockout and Mecp2 knockout mouse hippocampi had increased abundance of acetylated FOXO3. The MECP2R306C mutation occurs in Rett syndrome patients and interferes with the interaction between MECP2 and the complex of HDAC3 and NCoR (a transcriptional repression complex). Analysis of neural progenitor cells generated from inducible pluripotent stem cells from a patient with this mutation showed that HDAC3 binding and FOXO3 binding to selected promoters—which were also down-regulated in the Hdac3 knockout mice—was reduced and FOXO3 acetylation was increased. Thus, HDAC3 has a positive role in regulating gene expression in the hippocampus by deacetylating FOXO3, a role relevant to Rett syndrome.

Mahgoub et al. found that postnatal knockout of both Hdac1 and Hdac2 in the forebrain (cortex, hippocampus, and striatum) of mice resulted in increased apoptosis in the cortex and hippocampus but not striatum, weight loss, and early death at 9 weeks of age. At 6 weeks old these double-knockout mice had anxiety-like behaviors and by 7 weeks developed facial and neck lesions as result of excessive grooming behavior, a phenotype also associated with Sapap3 knockout. Sapap3 is also known as Dlgap3 and is a postsynaptic adaptor protein. Adenovirus-mediated knockout of Hdac1 and Hdac2 in the striatum did not reduce life span, weight, or cause apoptosis in the brain but did recapitulate the excessive grooming behavior, indicating that the function of these enzymes in the striatum was responsible for this abnormal behavior. Chromatin immunoprecipitation analysis of striatum identified MeCP2 as bound to the Sapap3 promoter, and Mecp2 knockout mice have decreased Sapap3 expression and exhibit excessive grooming. Adenovirus-mediated restoration of Sapap3 in the striatum of Mecp2 knockout mice reduced grooming behavior to that of control animals without altering other phenotypes associated with Mecp2 knockout. Thus, Sapap3 may be a key target contributing to one of the behavioral abnormalities associated with Rett syndrome.

Together, these studies illustrate several important signaling concepts and translation caveats. The presence of HDACs at a promoter cannot be interpreted as a “repressive” mark as indicated by the increase in gene expression associated with HDAC3 at promoters stimulated by FOXO3. Disorders that involved aberrant signaling proteins present in multiple regions of the brain may involve different interacting partners and require different strategies for therapeutic intervention depending on the brain region that is producing the symptom being treated. Global HDAC inhibition may cause neuronal toxicity so should be used with care if the drugs cross the blood-brain barrier.

A. Nott, J. Cheng, F. Gao, Y.-T. Lin, E. Gjoneska, T. Ko, P. Minhas, A. V. Zamudio, J. Meng, F. Zhang, P. Jin, L.-H. Tsai, Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat. Neurosci. 19, 1497–1505 (2016). [PubMed]

M. Mahgoub, M. Adachi, K. Suzuki, X. Liu, E. T. Kavalali, M. H. Chahrour, L. M. Monteggia, MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors. Nat. Neurosci. 19, 1506–1512 (2016). [PubMed]

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