Neural microexons, many of which are regulated by the neuronal-specific splicing factor nSR100/SRRM4, were found to be frequently dysregulated in the brains of individuals with ASD; this dysregulation was associated with reduced levels of nSR100 (Irimia et al., 2014). nSR100/Srrm4 haploinsufficiency in mice resulted in misregulated splicing patterns, autistic features such as sensory hypersensitivity and altered social behavior, and impaired synaptic transmission and excitability (Quesnel-Vallieres et al., 2016).
Molecular Function
SRRM4 promotes alternative splicing and inclusion of neural-specific exons in target mRNAs. This splicing factor is specifically required for neural cell differentiation.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
A highly conserved program of neuronal microexons is misregulated in autistic brains.
nSR100/SRRM4 haplo-insufficient mice with reduced levels of the neuronal splicing regulator protein (SRRM4) and decreased levels of the components of its target splicing program display neurodevelopmental defects and altered synaptic transmission, neuronal excitability, social behaviors, synaptic density and signaling, in a sexually dimorphic manner.
References
Type
Title
Author, Year
Primary
Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice harboring a homozygous frameshift deletion mutation spanning exons 7 and 8 of the SRRM4 gene.
Allele Type: Targeted
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice harboring a heterozygous frameshift deletion mutation spanning exons 7 and 8 of the SRRM4 gene. Heterozygous SRRM4 deletion mutant mice were crossed with Thy1-EGFP mouse line (PMID 11086982) to study dendritic spine density.
Allele Type: Targeted
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Description: Srrm4 mutant mice with a homozygous deletion spanning exons 7 and 8, show abnormal splicing of arvcf, ppfia2, slit2, dnm2, ptprd, synj1, dync2h1, pus7, vav2, itsn1, rapgef6, vps13c, nbea, shank1, smynd8, compared to wildtype controls. srrm4 mutant mice with a homozygous deletion spanning exons 7 and 8, show increased skipping of microexons in the forebrain as in activated neurons.
Exp Paradigm: Vast-tools software was used to detect and quantify alternative splicing from rna-seq data. number of alternative splicing events with percent spliced in (psi) was measured. neuronal activity dependent splicing of microexons was measured in mouse forebrain
Description: Srrm4 mutant mice with a homozygous deletion spanning exons 7 and 8, show negliglble expression of srrm4 protein compared to that in wildtype controls.
Exp Paradigm: Alpha tubulin is used as loading control.-western blot: cortex
Description: Srrm4 mutant mice with a homozygous deletion spanning exons 7 and 8, show negliglble expression of srrm4 protein compared to that in wildtype controls.
Exp Paradigm: Alpha tubulin is used as loading control.- quantitative pcr (qrt-pcr)
Description: Srrm4 haploinsufficient mice with the neuron specific thy1-egfp reporter show increase in the number of thin dendritic spines that lack the bulbous head characteristic of mature, functional spines, in the somatosensory cortex, compared to wildtype controls. mushroom, bulbous and filopodia dendritic spines show no change in number in srrm4 haploinsufficient mice compared to wildtype controls.
Exp Paradigm: Dendrites from layer v-vi pyramidal neurons in the somatosensory cortex were imaged from coronal slices. spines were counted on dendritic segments of approximately 35 microm.
Description: Srrm4 haploinsufficient mice show increased number of parvalbumin positive interneurons in the somatosensory cortex compared to wildtype controls.
Exp Paradigm: Pv
Description: Srrm4 haploinsufficient mice show decreased miniature excitatory epsp frequency compared to wildtype controls.
Exp Paradigm: Recordings were done on layer ii/iii pyramidal neurons of the somatosensory cortex in cortical slices placed in artificial cerebrospinal fluid.
Description: Srrm4 haploinsufficient mice show slight decrease in amplitudes of a- and b- waves in erg recordings compared to wildtype controls.
Exp Paradigm: Reference electrode was inserted subcutaneously into the top of the head between the ears and eye electrodes rested on the corneas of each respective eye; b- and a-waves were measured from stimulations at 0.25 cd*s/m2 and 10 cd*s/m2.
Description: Srrm4 haploinsufficient mice show decreased spontaneous excitatory epsp frequency compared to wildtype controls.
Exp Paradigm: Recordings were done on layer ii/iii pyramidal neurons of the somatosensory cortex in cortical slices placed in artificial cerebrospinal fluid.
Description: Srrm4 haploinsufficient mice show decreased firing of evoked action potentials compared to wildtype controls.
Exp Paradigm: The number of action potentials recorded when applying increasing steps of current injections for 500 ms were quantified.
Description: Srrm4 haploinsufficient mice show decreased miniature inhibitory mipsp frequency compared to wildtype controls.
Exp Paradigm: Recordings were done on layer ii/iii pyramidal neurons of the somatosensory cortex in cortical slices placed in artificial cerebrospinal fluid.
Description: Srrm4 haploinsufficient mice show significant increase in the amplitude of the startle response and a decrease in the prepulse inhibition of the startle response, compared to wildtype controls, indicating sensory hypersensitivity.
Exp Paradigm: After an acclimation period of 5 minutes, mice were presented with 20 ms pre-pulses of varying intensities (70, 75, 80 and 85 db) alone or preceding a 120 db, 40-60 ms pulse by 50-120 ms.
Description: Srrm4 haploinsufficient mice show slight decrease in amplitudes of a- and b- waves in erg recordings compared to wildtype controls.
Exp Paradigm: Reference electrode was inserted subcutaneously into the top of the head between the ears and eye electrodes rested on the corneas of each respective eye; b- and a-waves were measured from stimulations at 0.25 cd*s/m2 and 10 cd*s/m2.
Description: Srrm4 haploinsufficient mice show significant increase in the amplitude of the startle response and a decrease in the prepulse inhibition of the startle response, compared to wildtype controls, indicating sensory hypersensitivity.
Exp Paradigm: After an acclimation period of 5 minutes, mice were presented with 20 ms pre-pulses of varying intensities (70, 75, 80 and 85 db) alone or preceding a 120 db, 40-60 ms pulse by 50-120 ms.
Description: Srrm4 haploinsufficient mice show a decrease in social interaction measured by nose to nose sniffing, compared to wildtype controls.
Exp Paradigm: Reciprocal interaction test was performed after at least 30 min of social isolation. mice unfamiliar to each other were allowed to interact for 10 min in a clean cage.
Description: Srrm4 haploinsufficient mice show a decrease in social approach measured by an increase in the time spent with an inanimate object over an unfamiliar mouse, compared to wildtype controls.
Exp Paradigm: Mice were given 10 min to interact with an object or a stranger mouse for the social choice test, followed by an additional 10 min to interact with a familiar mouse or a new stranger mouse for the social novelty test.
Description: Srrm4 haploinsufficient mice show a decrease in social memory, measured by the decrease in time spent with an unfamiliar mouse over a familiar mouse or neutral territory, compared to wildtype controls.
Exp Paradigm: Mice were given 10 min to interact with a familiar mouse or a new stranger mouse for the social novelty test. social novelty was measured by time spent in chamber with familiar mouse or in neutral chamber/time spent in chamber with stranger mouse.
Description: Srrm4 haploinsufficient mice show abnormal splicing of arvcf, ppfia2, slit2, dnm2, ptprd, synj1, dync2h1, pus7, vav2, itsn1, rapgef6, vps13c, nbea, shank1, smynd8, compared to wildtype controls.
Exp Paradigm: Vast-tools software was used to detect and quantify alternative splicing from rna-seq data. number of alternative splicing events with percent spliced in (psi) was measured.
Description: Srrm4 haploinsufficient mice show srrm4 transcript and protein expression at a level approaximately half of that in wildtype controls. srrm4 protein levels are reduced in response to neuronal activation. the protein undergoes proteasomal degradation.
Exp Paradigm: Alpha tubulin is used as loading control.-western blot
Description: Srrm4 haploinsufficient mice show srrm4 transcript and protein expression at a level approaximately half of that in wildtype controls. srrm4 protein levels are reduced in response to neuronal activation. the protein undergoes proteasomal degradation.
Exp Paradigm: Alpha tubulin is used as loading control.- quantitative pcr (qrt-pcr): cortex
