Related Experiment Video
Updated: Jul 18, 2025
10:25
Using the E1A Minigene Tool to Study mRNA Splicing Changes
Published on: April 22, 2021
4.9K
Neuronal SAM68 differentially regulates alternative last exon splicing and ensures proper synapse development and
Mohamed Darwish1, Masatoshi Ito2, Yoko Iijima3
1Division of Basic Medical Science and Molecular Medicine, Department of Molecular Life Science, School of Medicine, Tokai University, Kanagawa, Japan; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
The Journal of Biological Chemistry
|August 18, 2023
Summary
SAM68 regulates alternative last exon (ALE) splicing in neurons, impacting synapse development. Aberrant splicing of protocadherin-15 (Pcdh15) creates soluble forms that disrupt synaptic function.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Alternative splicing in the 3' untranslated region (3'UTR) is vital for biological processes.
- SAM68 is a splicing regulator controlling 3'UTR isoform diversity via alternative last exon (ALE) selection.
- Mechanisms and significance of tissue-specific 3' end splicing remain unclear.
Purpose of the Study:
- To investigate SAM68's role in neuronal ALE splicing.
- To elucidate the mechanisms and functional consequences of Pcdh15 ALE splicing.
- To understand the impact of altered Pcdh15 isoforms on synapse development.
Main Methods:
- Investigated SAM68-dependent ALE splicing in neuronal cells.
- Analyzed SAM68 interaction with U1 small nuclear ribonucleoprotein (snRNP).
- Studied Pcdh15 ALE splicing regulation by calcium/calmodulin-dependent protein kinase signaling.
- Assessed effects of soluble Pcdh15 on synapse formation and protein interactions.
Main Results:
- SAM68 regulates ALE splicing in a dose-dependent manner, with differential regulation in neurons.
- SAM68 controls interleukin-1 receptor-associated protein splicing via U1 snRNP.
- Pcdh15 ALE splicing is U1 snRNP-independent but modulated by Ca2+/calmodulin-dependent protein kinase signaling.
- Aberrant Pcdh15 ALE splicing yields a soluble isoform that disrupts synaptic localization and function, particularly affecting inhibitory synapses.
- Soluble Pcdh15 interacts with α-neurexins and impairs neuroligin-2-induced synapse formation.
Conclusions:
- SAM68 plays a critical role in neuron-specific alternative 3'UTR splicing.
- Aberrant Pcdh15 splicing contributes to synaptic dysfunction in neuropsychiatric disorders.
- Alternative 3'UTR isoform selection is a key mechanism in synapse development and function.
Related Concept Videos
02:18Alternative RNA Splicing
21.3K
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
21.3K
01:32RNA Splicing
56.5K
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
56.5K
02:41Chromatin Structure Regulates pre-mRNA Processing
7.0K
In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
The chromatin structure, especially...
The chromatin structure, especially...
7.0K
01:36What is Gene Expression?
8.6K
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised of nucleotides and proteins are comprised of amino acids, a mediator is required to convert the information encoded in DNA into proteins. This mediator is the messenger RNA (mRNA). mRNA copies the blueprint from DNA by a process called transcription. In eukaryotes, transcription occurs in the nucleus by complementary base-pairing with the DNA template. The mRNA is then...
8.6K
01:36Pre-mRNA Processing: RNA Splicing
5.3K
5.3K
02:32Exon Recombination
3.6K
The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes.
Exon shuffling follows “splice frame rules.” Each exon...
Exon shuffling follows “splice frame rules.” Each exon...
3.6K