The long-term objective of this application is to increase our knowledge of how the growth and guidance of axons is regulated during embryonic development. The functioning nervous system requires precise interconnections between neurons, and this application aims to dissect the guidance mechanisms of a set of axons that pioneers the first longitudinal tract in the mouse forebrain, the tract of the postoptic commissure (tpoc). This tract is foundational, as it lays down the pathway followed by a multitude of later ascending and descending axons. Therefore the tpoc is crucial to understanding the formation of neural circuitry in the basal forebrain. Recently, we discovered that the tpoc axons make severe guidance errors in embryos mutant for the transcription factor Pax6. This mutant provides an opportunity to discover how early patterning genes, such as Pax6, might provide positional information in the form of guidance cues. The main approach will be to challenge the axons by creating altered patterns of Pax6 in the developing brain. Analysis of axon responses will reveal where and how Pax6 acts to influence axon outgrowth. To alter Pax6 expression patterns, several different strategies will be used. A new electroporation method will be used to target gene expression in intact embryos, including restoration of Pax6 to local regions of Pax6 mutant embryos, expansion of Pax6 expression in wild type embryos, and interference with endogenous Pax6 by targeted expression of dominant negative alleles of Pax6. The effect of altered Pax6 expression will also be examined in chimeric embryos with a mixture of wild type and Pax6 mutant cells, and in mutant mice that selectively lack Pax6 in only one cell type. In an initial analysis of downstream targets of Pax6, the axon guidance role of the Pax6-dependent cell adhesion molecule R-cadherin will also be examined by in vitro approaches and embryo electroporation experiments. This work will contribute to our knowledge of both the normal and mutant developing nervous system. Developmental defects underlie many devastating neurological disorders, and understanding the mechanisms of axon pathfinding and neuronal patterning may eventually lead to strategies for prevention or treatment of birth defects. In addition, the mechanisms of axon growth during development may give insight into how regeneration of the nervous system may be stimulated following trauma or disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038069-03
Application #
6629126
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (01))
Program Officer
Henken, Deborah B
Project Start
2001-02-21
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$194,387
Indirect Cost
Name
University of Nevada Reno
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Shoja-Taheri, Farnaz; DeMarco, Arielle; Mastick, Grant S (2015) Netrin1-DCC-Mediated Attraction Guides Post-Crossing Commissural Axons in the Hindbrain. J Neurosci 35:11707-18
Kim, Minkyung; Farmer, W Todd; Bjorke, Brielle et al. (2014) Pioneer midbrain longitudinal axons navigate using a balance of Netrin attraction and Slit repulsion. Neural Dev 9:17
Kim, Minkyung; Roesener, Andrew P; Mendonca, Philipe R F et al. (2011) Robo1 and Robo2 have distinct roles in pioneer longitudinal axon guidance. Dev Biol 358:181-8
Dugan, James P; Stratton, Andrea; Riley, Hilary P et al. (2011) Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit/Robo signals. Mol Cell Neurosci 46:347-56
Ricaño-Cornejo, Itzel; Altick, Amy L; García-Peña, Claudia M et al. (2011) Slit-Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain. J Neurosci Res 89:1531-41
Mastick, Grant S; Farmer, W Todd; Altick, Amy L et al. (2010) Longitudinal axons are guided by Slit/Robo signals from the floor plate. Cell Adh Migr 4:337-41
Andrews, Gracie L; Tanglao, Shawna; Farmer, W Todd et al. (2008) Dscam guides embryonic axons by Netrin-dependent and -independent functions. Development 135:3839-48
Brill, Monika S; Snapyan, Marina; Wohlfrom, Hilde et al. (2008) A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb. J Neurosci 28:6439-52
Farmer, W Todd; Altick, Amy L; Nural, Hikmet Feyza et al. (2008) Pioneer longitudinal axons navigate using floor plate and Slit/Robo signals. Development 135:3643-53
Nural, Hikmet Feyza; Todd Farmer, W; Mastick, Grant S (2007) The Slit receptor Robo1 is predominantly expressed via the Dutt1 alternative promoter in pioneer neurons in the embryonic mouse brain and spinal cord. Gene Expr Patterns 7:837-45

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