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Mechanisms of axonal pathfinding during nervous system development

Award Number: R15HD084241
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2021

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Mechanisms of axonal pathfinding during nervous system development - Despite the prevalence of genetically heritable forms of intellectual disability (ID), only a handful of genes have been causally linked to ID. Previous studies identified inactivating recessive mutations in the human gene ZC3H14 that are linked to intellectual disability. ZC3H14 binds to polyadenosine RNA and controls the length of the poly(A) tail, suggesting that ZC3H14 functions in the post-transcriptional control of gene expression. To better understand the molecular and cellular consequences of ZC3H14 loss we created a ZC3H14 ID model using the fruit fly, Drosophila melanogaster. The D. melanogaster ortholog of ZC3H14, called Nab2, also binds polyadenosine RNA, is required for control of poly(A) tail length, and is essential for viability and nervous system development. Importantly, expression of either fly Nab2 or human ZC3H14 in the neurons of Nab2 null flies can rescue poly(A) tail length and viability defects, suggesting that Nab2 and ZC3H14 are functional orthologs. This trans-species rescue also validates our use of flies to study the overall cellular function of ZC3H14. We have also recently demonstrated that alterations in the level of fly Nab2 cause axon mis- projection defects in both the mushroom bodies, a central region of the fly brain required for associative memory formation, and photoreceptor neurons in the fly eye. Presumably, these mis-targeting phenotypes are the result of defects in the post-transcriptional regulation of specific transcripts required for axonal pathfinding. Interestingly, loss of Nab2 causes alterations in the expression of several enzymes responsible for control of cyclic nucleotide levels. Previous studies have demonstrated that cAMP and cGMP play critical roles in mediating the strength of attractive and repulsive navigational cues during axon pathfinding. Mathematical modeling from other labs corroborates these experimental findings and suggests that maintenance of precise cyclic nucleotide levels is necessary for the dynamic control of pathfinding decisions. Importantly, we show preliminary data here in support of that hypothesis and seek to extend these studies using an in vivo Drosophila model of axon guidance. Specifically, it is our overall model that cyclic nucleotide levels are precisely regulated during pathfinding in order that extending growth cones can dynamically respond to extracellular guidance cues. In the current proposal we aim to examine the overall necessity of cyclic nucleotide second messengers in axonal guidance. Aim 1 of this proposal will use a combination of genetic, cell biology, and biochemical techniques to uncover the molecular mechanism by which Nab2 controls expression of enzymes responsible for maintaining intracellular levels of cAMP and/or cGMP during axon pathfinding. In Aim 2 we will extend these studies to test whether directly disrupting cyclic nucleotide homeostasis results in pathfinding defects in vivo. Given the conservation between many of the enzymes involved in cyclic nucleotide biosynthesis, these studies have the potential to greatly increase our understanding of how cyclic nucleotide second messengers control axonal growth and synapse selection.


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: 2023 ( Subtotal = -$1,037 )
2023	2016	THE COLLEGE OF WOOSTER	1101 N BEVER ST	WOOSTER	OH	44691	WAYNE	USA	Child Health and Human Development Extramural Research	000	1	10/1/2022	NEW	-$1,037
														Subtotal = -$1,037

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2016	COLLEGE OF WOOSTER, THE	1101 N BEVER ST	WOOSTER	OH	44691	WAYNE	USA	Child Health and Human Development Extramural Research	000	1	2/1/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	THE COLLEGE OF WOOSTER	1189 BEALL AVE	WOOSTER	OH	44691	WAYNE	USA	Child Health and Human Development Extramural Research	000	1	6/24/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $284,276 )
2016	2016	COLLEGE OF WOOSTER	**	WOOSTER	OH	44691	WAYNE	USA	Child Health and Human Development Extramural Research	000	1	8/5/2016	NEW	$284,276
														Subtotal = $284,276

Grand Total All Awards = $283,239

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Mechanisms of axonal pathfinding during nervous system development

Award Number: R15HD084241

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2021

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