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Mechanical catalysis of calcineurin dependent cofilin activity during chemotropic axon growth: a new role for PKC in coordinating actin dynamics and myosin II contractility

Award Number: R01NS028695
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The ADF/cofilin family of proteins play a critical role in actin filament turnover essential to all forms of eukaryotic cell motility. Despite a vast literature on signaling pathways controlling cofilin activity, assessing the function of this important protein in living cells has been hampered by lack of real time assays of cofilin function. Using a novel real time assay for assessing cofilin activity and actin dynamics simultaneously by quantitative fluorescent speckle microscopy (qFSM), we have discovered that mechanical stress imposed on treadmilling actin networks increases cofilin activity with dramatic effects on actin turnover rates that depend on the level of stress. Low stress levels are associated with increases in actin turnover and treadmilling rates that are associated with chemotropic growth; in contrast, stress levels above a critical threshold lead to catastrophic decreases in actin network density resulting in neurite retraction. We have been studying mechanical effects on cofilin activity in the context of serotonin (5-HT) evoked neurite growth responses mediated by classical G(q) subtype GPCRs, which activate phospholipase C to generate IP3 and DAG signals. 5-HT evokes IP3 dependent Ca release from intracellular stores and cofilin activation by a Ca¿calcineurin signaling cascade. We now have evidence that DAG production results in PKC dependent increases in non-muscle myosin II activity. This in turn generates local network stress and mechano-catalytic activation of cofilin resulting in local alteration of F-actin structure and network turnover rates. Effects on actin structure also depend on the level of PKC activation. PKC has other known roles including regulation of microtubule (MT) dynamics in growth cones and since MTs are the transport substrate for ER/Ca stores, MT dynamics regulate the functional topography of IP3 dependent Ca release involved in 5-HT dependent growth. PKC can also potentiate integrin based cell adhesion and thereby affect traction forces involved in neuronal growth. We propose to investigate PKC as a signaling node that coordinates: 1) myosin II contractility, 2) actin turnover via cofilin mechano-catalysis, 3) Ca release topography via regulation of microtubule/ER dynamics, and 4) ultimately, traction force production during axon growth. These studies will provide a mechanistic framework for understanding how cofilin enables functional crosstalk between actin dynamics and myosin II contractility during chemotropic growth responses. The results will have interesting implications regarding the key role PKC plays in neuronal growth and neurodegenerative disease.


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 = $361,191 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	31	3/5/2024	NON-COMPETING CONTINUATION	$361,191
														Subtotal = $361,191

Issue Date FY: 2023 ( Subtotal = $402,073 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	30	4/1/2023	NON-COMPETING CONTINUATION	$402,073
2023	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	10/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,073

Issue Date FY: 2022 ( Subtotal = $418,750 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	4/6/2022	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2021 ( Subtotal = $588,804 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	28	8/31/2021	COMPETING CONTINUATION	$170,054
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	28	5/10/2021	COMPETING CONTINUATION	$418,750
														Subtotal = $588,804

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	1/14/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $364,219 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	27	8/2/2017	NON-COMPETING CONTINUATION	$364,219
2017	2016	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	26	12/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$46,178
2017	2015	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	12/12/2016	NON-COMPETING CONTINUATION	-$46,178
														Subtotal = $364,219

Issue Date FY: 2016 ( Subtotal = $364,219 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	8/2/2016	EXTENSION WITH OR WITHOUT FUNDS	$364,219
														Subtotal = $364,219

Issue Date FY: 2015 ( Subtotal = $364,219 )
2015	2015	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	8/3/2015	NON-COMPETING CONTINUATION	$364,219
														Subtotal = $364,219

Issue Date FY: 2014 ( Subtotal = $360,300 )
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	8/21/2014	NON-COMPETING CONTINUATION	$360,300
														Subtotal = $360,300

Issue Date FY: 2013 ( Subtotal = $363,948 )
2013	2013	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	23	9/2/2013	COMPETING CONTINUATION	$363,948
2013	2012	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	8/30/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $363,948

Issue Date FY: 2012 ( Subtotal = $348,567 )
2012	2012	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	2/2/2012	NON-COMPETING CONTINUATION	$348,567
														Subtotal = $348,567

Issue Date FY: 2011 ( Subtotal = $348,835 )
2011	2011	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	1/26/2011	NON-COMPETING CONTINUATION	$320,359
2011	2011	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	6/7/2011	NON-COMPETING CONTINUATION	$28,476
2011	2009	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Trans-NIH Recovery Act Research Support	002	19	9/8/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $348,835

Issue Date FY: 2010 ( Subtotal = $352,654 )
2010	2010	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	1/20/2010	NON-COMPETING CONTINUATION	$352,654
														Subtotal = $352,654

Issue Date FY: 2009 ( Subtotal = $456,590 )
2009	2009	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	4/2/2009	NON-COMPETING CONTINUATION	$35,647
2009	2009	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	1/23/2009	NON-COMPETING CONTINUATION	$320,819
2009	2009	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Trans-NIH Recovery Act Research Support	002	19	9/23/2009	SUPPLEMENT FOR EXPANSION	$100,124
														Subtotal = $456,590

Issue Date FY: 2008 ( Subtotal = $276,306 )
2008	2008	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	1/18/2008	COMPETING CONTINUATION	$276,306
														Subtotal = $276,306

Issue Date FY: 2006 ( Subtotal = $378,857 )
2006	2006	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	5/26/2006	NON-COMPETING CONTINUATION	$378,857
														Subtotal = $378,857

Issue Date FY: 2005 ( Subtotal = $387,984 )
2005	2005	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	6/22/2005	NON-COMPETING CONTINUATION	$387,984
														Subtotal = $387,984

Issue Date FY: 2004 ( Subtotal = $387,994 )
2004	2004	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	4/23/2004	NON-COMPETING CONTINUATION	$387,994
														Subtotal = $387,994

Issue Date FY: 2003 ( Subtotal = $388,003 )
2003	2003	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	8/6/2003	NON-COMPETING CONTINUATION	$388,003
														Subtotal = $388,003

Issue Date FY: 2002 ( Subtotal = $362,977 )
2002	2002	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	NEW HAVEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	9/30/2002	COMPETING CONTINUATION	$362,977
														Subtotal = $362,977

Issue Date FY: 2001 ( Subtotal = $327,380 ) (Continued on the next page)
Grand Total All Awards = $8,434,440

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Mechanical catalysis of calcineurin dependent cofilin activity during chemotropic axon growth: a new role for PKC in coordinating actin dynamics and myosin II contractility

Award Number: R01NS028695

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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