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Mechanism and consequence of intron-retention in the adult brain

Award Number: R01MH101440
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Mechanism and consequence of intron-retention in the adult brain - Project Summary Our efforts to delineate the biochemical processes that convert a transient experience to a persistent memory led to the discovery that functional aggregation of a Drosophila RNA-binding protein Orb2A is critical for the animals’ ability to form and retain a memory. During the previous grant period, in our effort to decipher regulation of Orb2A aggregation, we discovered that the expression of Orb2A protein in the adult brain is controlled via a unique mechanism. The fully transcribed and polyadenylated Orb2A transcripts retain an intron and are stably expressed in the fly brain. The intron-retained Orb2A mRNA does not code for a protein, owing to multiple in frame stop codons. However, behavioral training that produces long-term but not short-term memory transiently increases the spliced protein-coding mRNA level. This splicing event, important for long-term memory, is mediated by a specific isoform of the splicing regulator Pasilla, psL. Intron retention (IR), a poorly studied form of alternative splicing, was thought to modulate gene expression primarily by degrading the mRNA, trapping it in the nucleus and thereby reducing protein expression. Our findings suggest that IR can be used in a novel way: to hold mRNA in a ‘poised state’, which can allow spatial and temporal integration of various signals to acutely increase protein expression to regulate memory. These observations led us to ask how prevalent IR is in the adult Drosophila brain, and what is the molecular basis of IR in the brain and how experience interacts with the intron-retention mechanisms to control protein expression and memory. We have performed poly(A) RNA-sequencing from wild type fly brains. The analysis provided some surprising results. First, 8.9% of all detectable introns, corresponding to 3031 genes, show ≥ 25% retention in wildtype fly brain. These includes 55 genes with role in learning and memory. A recent genome-wide study revealed ~6% of fully transcribed and polyadenylated transcripts in the mouse brain also retains an intron. Remarkably, the mouse orthologues of some the Drosophila genes, including Orb2 orthologue CPEB2, also retains intron. Second, like Orb2, aggregate-prone prion-like proteins are significantly overrepresented in the intron retained genes. This includes a novel prion-like phosphatase we have recently identified. From adult brain, we have identified proteins that bind to a retained intron and interacts with psL. In the current proposal we intend to investigate how memory-related stimuli activate p38a, a putative kinase of psL, how behavioral stimuli effect psL interaction with its binding partners, what sequence motifs in a retained motif influence intron retention, how intron retention controls expression of aggregate-prone proteins and how perturbation of each of these processes effects animals ability to form and retain memory. These studies would provide insight into the IR-mediated control of protein expression, a novel gene regulatory mechanism, as well as the molecular basis of memory and the regulation of aggregate-prone proteins.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $412,500 )
2024	2024	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	10	8/14/2024	NON-COMPETING CONTINUATION	$41,250
2024	2024	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	10	2/22/2024	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $412,500

Issue Date FY: 2023 ( Subtotal = $412,500 )
2023	2023	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	9	2/28/2023	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2022 ( Subtotal = $412,500 )
2022	2022	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	8	2/9/2022	NON-COMPETING CONTINUATION	$371,250
2022	2022	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH ST	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	8	5/12/2022	NON-COMPETING CONTINUATION	$41,250
														Subtotal = $412,500

Issue Date FY: 2021 ( Subtotal = $412,500 )
2021	2021	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	7	3/1/2021	NON-COMPETING CONTINUATION	$412,500
2021	2018	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	5	6/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $412,500

Issue Date FY: 2020 ( Subtotal = $412,500 )
2020	2020	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	002	6	4/30/2020	COMPETING CONTINUATION	$412,500
2020	2018	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	5	3/19/2020	NON-COMPETING CONTINUATION	$0
2020	2018	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	5	4/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $412,500

Issue Date FY: 2018 ( Subtotal = $412,500 )
2018	2018	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	5	4/27/2018	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2017 ( Subtotal = $412,500 )
2017	2017	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	4	8/3/2017	NON-COMPETING CONTINUATION	$41,250
2017	2017	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 E 50TH	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	4	3/10/2017	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $412,500

Issue Date FY: 2016 ( Subtotal = $412,500 )
2016	2016	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 EAST 50TH STREET	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	3	3/16/2016	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2015 ( Subtotal = $412,500 )
2015	2015	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 EAST 50TH STREET	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	2	4/30/2015	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2014 ( Subtotal = $412,500 )
2014	2014	STOWERS INSTITUTE FOR MEDICAL RESEARCH	1000 EAST 50TH STREET	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	1	7/18/2014	NEW	$412,500
														Subtotal = $412,500

Grand Total All Awards = $4,125,000

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Mechanism and consequence of intron-retention in the adult brain

Award Number: R01MH101440

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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