Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Bach, Snow; Shovlin, Stephen; Moriarty, M.; Bardoni, Barbara; Tropea, Daniela

doi:10.3389/fncel.2021.764761

Cited by 15 publications

(6 citation statements)

References 183 publications

(207 reference statements)

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“…We furthermore identified FMR1 (FMRP) as a SPOC-dependent interactor of SHARP. An expansion of CGG-repeats within FMR1 leads to the reduction or abolishment of its expression and is the cause of fragile X syndrome, which can manifest as mild to severe intellectual disability and autism spectrum disorder 51 . On a molecular level, FMR1 is an RNA-binding protein that binds m 6 A mRNA, regulates mRNA export, and acts as a translational repressor to modulate the amount of protein production 35 , 52 .…”

Section: Discussionmentioning

confidence: 99%

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

et al. 2023

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The heptad repeats of the C-terminal domain (CTD) of RNA polymerase II (Pol II) are extensively modified throughout the transcription cycle. The CTD coordinates RNA synthesis and processing by recruiting transcription regulators as well as RNA capping, splicing and 3’end processing factors. The SPOC domain of PHF3 was recently identified as a CTD reader domain specifically binding to phosphorylated serine-2 residues in adjacent CTD repeats. Here, we establish the SPOC domains of the human proteins DIDO, SHARP (also known as SPEN) and RBM15 as phosphoserine binding modules that can act as CTD readers but also recognize other phosphorylated binding partners. We report the crystal structure of SHARP SPOC in complex with CTD and identify the molecular determinants for its specific binding to phosphorylated serine-5. PHF3 and DIDO SPOC domains preferentially interact with the Pol II elongation complex, while RBM15 and SHARP SPOC domains engage with writers and readers of m6A, the most abundant RNA modification. RBM15 positively regulates m6A levels and mRNA stability in a SPOC-dependent manner, while SHARP SPOC is essential for its localization to inactive X-chromosomes. Our findings suggest that the SPOC domain is a major interface between the transcription machinery and regulators of transcription and co-transcriptional processes.

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Section: Discussionmentioning

confidence: 99%

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

et al. 2023

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“…In MECP2 duplication syndrome, also associated with ASD, higher visual acuity and contrast sensitivity in neurons from V1 was described 74 . It is worth mentioning that these two models are considered two monogenic neurodevelopmental disorders, whereby ASD may not be considered a core symptom but may have a high prevalence 3 , 52 , 53 , 70 . These reports support the idea that there might be alterations in visual processing in neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of Shank3 increases the orientation selectivity of V1 neurons

Ortiz-Cruz

Marquez

Linares-García

et al. 2022

Sci Rep

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose hallmarks are social deficits, language impairment, repetitive behaviors, and sensory alterations. It has been reported that patients with ASD show differential activity in cortical regions, for instance, increased neuronal activity in visual processing brain areas and atypical visual perception compared with healthy subjects. The causes of these alterations remain unclear, although many studies demonstrate that ASD has a strong genetic correlation. An example is Phelan–McDermid syndrome, caused by a deletion of the Shank3 gene in one allele of chromosome 22. However, the neuronal consequences relating to the haploinsufficiency of Shank3 in the brain remain unknown. Given that sensory abnormalities are often present along with the core symptoms of ASD, our goal was to study the tuning properties of the primary visual cortex to orientation and direction in awake, head-fixed Shank3+/− mice. We recorded neural activity in vivo in response to visual gratings in the primary visual cortex from a mouse model of ASD (Shank3+/− mice) using the genetically encoded calcium indicator GCaMP6f, imaged with a two-photon microscope through a cranial window. We found that Shank3+/− mice showed a higher proportion of neurons responsive to drifting gratings stimuli than wild-type mice. Shank3+/− mice also show increased responses to some specific stimuli. Furthermore, analyzing the distributions of neurons for the tuning width, we found that Shank3+/− mice have narrower tuning widths, which was corroborated by analyzing the orientation selectivity. Regarding this, Shank3+/− mice have a higher proportion of selective neurons, specifically neurons showing increased selectivity to orientation but not direction. Thus, the haploinsufficiency of Shank3 modified the neuronal response of the primary visual cortex.

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“…We furthermore identified FMR1 (FMRP) as a SPOC-dependent interactor of SHARP. An expansion of CGG-repeats within FMR1 leads to reduction or abolishment of its expression and is the cause of fragile X syndrome, which can manifest as mild to severe intellectual disability and autism spectrum disorder 47 . On a molecular level, FMR1 is an RNA-binding protein that binds m6A mRNA, regulates mRNA export and acts as a translational repressor to modulate the amount of protein production 34, 48 .…”

Section: Discussionmentioning

confidence: 99%

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

Appel

Grishkovskaya

Benedum

et al. 2022

Preprint

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The heptarepeats of the C-terminal domain (CTD) of RNA polymerase II (Pol II) are extensively modified throughout the transcription cycle. The CTD coordinates RNA synthesis and processing by recruiting transcription regulation factors as well as RNA capping, splicing and 3end processing factors. The SPOC domain of PHF3 was recently identified as a new CTD reader domain specifically binding to phosphorylated serine-2 residues in adjacent CTD repeats. Here, we establish the SPOC domains of the human proteins DIDO, SHARP and RBM15 as phosphoserine binding modules that can act as CTD readers but also recognize other phosphorylated binding partners. We report the crystal structure of SHARP (SPEN) SPOC-CTD and identify the molecular determinants for its specific binding to phosphorylated serine-5. PHF3 and DIDO SPOC domains preferentially interact with the Pol II elongation complex, while RBM15 and SHARP SPOC domains engage with the m6A writer and reader proteins. Our findings establish the SPOC domain as a major interface between the transcription machinery and regulators of transcription and co-transcriptional processes.

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Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Cited by 15 publications

References 183 publications

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

Haploinsufficiency of Shank3 increases the orientation selectivity of V1 neurons

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

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