Biology subjects

Durham, M. A.

Publications and source records attributed to Durham, M. A..

3 recordsLinked to original sources

bioRxiv2025

Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease

Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid beta production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L)--yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused perinatal lethality, phenocopying, ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform-paralog interplay in studying regional vulnerability in neurodegenerative diseases.

molecular biology↗

bioRxiv2022

MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.

neuroscience↗

bioRxiv2019

Loss of Dnmt3a dependent methylation in inhibitory neurons impairs neural function through a mechanism that impacts Rett syndrome

Methylated cytosine is an effector of epigenetic gene regulation. In the mammalian brain, the DNA methyltransferase, Dnmt3a, is the sole \"writer\" of atypical non-CpG methylation (mCH), and methyl CpG binding protein 2 (MeCP2) is the only known \"reader\" for mCH. We set out to determine if MeCP2 is the sole reader for Dnmt3a dependent methylation by comparing mice lacking either Dnmt3a or MeCP2 in GABAergic inhibitory neurons. Loss of either the writer or the reader causes overlapping and distinct features from the behavioral to the molecular level. Loss of Dnmt3a results in global loss of mCH and a small subset of mCG sites resulting in more widespread transcriptional alterations and severe neurological dysfunction than seen upon MeCP2 loss. These data indicate that MeCP2 is responsible for reading part of the Dnmt3a dependent methylation in the brain. Importantly, the impact of MeCP2 on genes differentially expressed in both cKO models shows a strong dependence on mCH, but not Dnmt3a dependent mCG, consistent with mCH playing a central role in the pathogenesis of Rett Syndrome.

neuroscience↗