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Mechanism of mRNA Localization and Localized Translation in Neurons

Award Number: R01NS083085
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/03/1992
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Mechanism of mRNA Localization and Localized Translation in Neurons - ABSTRACT The neuron is the basic cellular unit of the brain. For neurons to work properly, they must be plastic and constantly capable of changing in response to stimuli, forming and stabilizing new connections. This process requires proteins to be added to the new synaptic contact, and this in turn results from the targeting of mRNA to these sites of activity, as we have shown in our previous work. This is the molecular basis of learning and memory since the synapse is stabilized by the production of proteins in response to stimulation that is important for its function and structural integrity. How this mRNA is regulated in neurons to make the right protein at the right place and time has been the subject of our investigations over the years of this funding. This proposal exploits the tools we developed during the last funding period to address how mRNA is regulated in dendrites. We have expended considerable effort in the generation of genetically engineered mice wherein the loci of three neuronally expressed genes important for learning and memory have been tagged with stem loops that, when expressed in the mRNA bind to fluorescent proteins. The single mRNAs expressed from these genes can be imaged in living cells and extended into live tissues. We have taken care to verify that the tagging is neutral: it does not alter the behavior or affect memory formation in the mice. One of these tags is for Arc, an immediate early gene in response to neuronal stimulation important for consolidating long term memory. Unlike the constitutive -actin mRNA, which we showed sits at the place where it was last stimulated for hours, Arc mRNA localizes only for a few minutes, and degrades soon after. The current proposal reports on the progress to solving how transiently localized mRNAs can impact long term changes at the stimulated spines. The surprise was that Arc undergoes cycles of localization and translation in response to a single stimulus. Even more incredible is that the translation occurs spatially at the same spot, so the mRNA in the next cycle finds the site of previous localization and builds up a continuous “hotspot” of localized protein synthesis. This in contrast to the β-actin mRNA, which persists at the stimulated site, awaiting the next signal, wherein it will initiate another round of proteins. Because β-actin is a structural protein, the synaptic contact is built up with rounds of translation, consistent with a learning and memory paradigm that relies on repetitive stimulation. The current proposal is directed towards understanding the kinetics of translation hotspots, and their spatial overlap for different mRNAs with distinct roles in plasticity. We crossed the β-actin and Arc mice to homozygosity where both mRNAs were individually detectable by different colored fluorochromes in the same neuron. We have learned from this mouse that the two mRNAs were handled differently by the neuron, and traveled in independent “granules”, likely resulting from differences in their associated proteins. For instance, β-actin mRNA bound the zipcode binding protein, ZBP1 (IMP1) whereas Arc mRNA instead bound the protein FMRP. Further progress will elucidate the protein composition of each granule in more detail. We have made two more mice during the last funding period: a GCN4 epitope tagged (“Suntag”) Arc mouse that will allow us to see the translation sites of Arc protein using a fluorescent single chain antibody in living cells and tissues (we developed this tag previously), and a CaMKII mouse where the mRNA is distinguishable from either β-actin mRNA or Arc mRNA by hybrid fluorescent tags. This allows us now to contrast how the neuron handles each mRNA, for example in its localization and translation. Over the last funding period, an unexpected result was that the CaMKII mRNA localized in the spines, unlike either Arc or β-actin mRNA, that stayed at the base of the spines. This indicated that subtleties in the localization of these mRNAs may underlie a physiological purpose. We intend to investigate this by determining the sequences that likely direct this mRNA into the spines. Ultimately, we intend to find the proteins bound specifically to these mRNAs and how they might affect the regulation of their respective mRNAs. This will use the technologies of RNA editing and proximity labeling, which will allow us to interrogate the associated RNAs and proteins that make each species of mRNA granule unique.


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 = $652,010 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	32	8/14/2024	NON-COMPETING CONTINUATION	$652,010
2024	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	30	10/25/2023	COMPETING CONTINUATION	$3,348
2024	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	10/25/2023	NON-COMPETING CONTINUATION	-$3,348
														Subtotal = $652,010

Issue Date FY: 2023 ( Subtotal = $676,333 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	31	8/15/2023	NON-COMPETING CONTINUATION	$676,333
														Subtotal = $676,333

Issue Date FY: 2022 ( Subtotal = $591,164 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	30	9/22/2022	COMPETING CONTINUATION	$665,821
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	11/19/2021	SUPPLEMENT FOR EXPANSION	-$74,657
														Subtotal = $591,164

Issue Date FY: 2021 ( Subtotal = $722,868 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	8/23/2021	NON-COMPETING CONTINUATION	$648,211
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	29	8/31/2021	SUPPLEMENT FOR EXPANSION	$74,657
														Subtotal = $722,868

Issue Date FY: 2020 ( Subtotal = $760,859 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	28	9/21/2020	NON-COMPETING CONTINUATION	$0
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	28	9/2/2020	NON-COMPETING CONTINUATION	$745,972
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	6/19/2020	SUPPLEMENT FOR EXPANSION	$14,887
														Subtotal = $760,859

Issue Date FY: 2019 ( Subtotal = $656,477 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	27	8/9/2019	NON-COMPETING CONTINUATION	$656,477
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	26	2/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$270,805
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	2/6/2019	NON-COMPETING CONTINUATION	-$270,805
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	25	6/7/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $656,477

Issue Date FY: 2018 ( Subtotal = $656,477 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	25	8/23/2018	NON-COMPETING CONTINUATION	$656,477
2018	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	2/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $656,477

Issue Date FY: 2017 ( Subtotal = $656,477 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	24	9/15/2017	COMPETING CONTINUATION	$656,477
2017	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	9/15/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $656,477

Issue Date FY: 2016 ( Subtotal = $559,574 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	23	8/2/2016	NON-COMPETING CONTINUATION	$559,574
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	2/1/2016	NON-COMPETING CONTINUATION	$45,000
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	2/1/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$45,000
														Subtotal = $559,574

Issue Date FY: 2015 ( Subtotal = $566,638 )
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	9/21/2015	NON-COMPETING CONTINUATION	-$566,638
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	8/14/2015	NON-COMPETING CONTINUATION	$566,638
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	22	9/22/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$566,638
														Subtotal = $566,638

Issue Date FY: 2014 ( Subtotal = $566,800 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	8/4/2014	NON-COMPETING CONTINUATION	$566,800
														Subtotal = $566,800

Issue Date FY: 2013 ( Subtotal = $578,411 )
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	9/9/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$578,411
														Subtotal = $578,411

Grand Total All Awards = $7,644,088

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Mechanism of mRNA Localization and Localized Translation in Neurons

Award Number: R01NS083085

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/03/1992

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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