A major goal in neurobiology is identifying functional neuronal pathways. Classical anatomical tracing techniques allow connectivity between brain regions to be determined. Lesion studies and anatomically restricted infusion of pharmacological agents have helped to identify the functional role of these brain regions at a gross level. The development of techniques for the genetic manipulation of the mouse during the past 15 years has greatly expanded our ability to probe the molecular mechanisms of biological function in a mammalian model system. However, one of the difficulties in the application of the genetic approach to the nervous system is the relative lack of ability to map molecular genetic changes onto the complex neuroanatomy of the brain. The goal of the current application is to develop a series of 48 driver lines for the generation of anatomically restricted and inducible gene knock-outs. For greatest genetic utility to the neuroscience community the strains will be developed on a pure C57BL/6 background. The most widely used tools for anatomically restricted and time dependent manipulation of gene function in the mouse are the CRE-recombinase and the tTA-transactivator, respectively, but very few driver lines are available to the neuroscience community. Furthermore, most CRE-driver lines do not allow strict temporal control, such as the ability to knock-out genes in adult tissues. We plan to use transgenic approaches to express CRE and tTA driven by the regulatory elements of 24 chosen genes. The default approach is targeting via homologous recombination in ES cells; vectors for pronuclear injections (including BACs) will also be utilized. The driver lines will allow us to achieve temporal and spatial control of recombinase activity in disparate regions of the nervous system. Driver lines will be validated by monitoring cell type and time dependent CRE activity. Behavioral studies will ensure that the transgenes do not affect neuronal function. The choice of the 24 driver loci represents the expertise of the four investigators involved in this application and are of relevance for the neuroscience community, covering sensory biology and pain, CMS and stem cell development, the limbic system, and learning and memory. From a clinical perspective the lines generated should be particularly relevant to the study of Neuropsychiatric disorders and addiction (eg. targeting the dopamine system) and neurodegenerative disorders (e.g. targeting the limbic system and adult stem cells). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH078833-03
Application #
7495585
Study Section
Special Emphasis Panel (ZMH1-ERB-L (06))
Program Officer
Nadler, Laurie S
Project Start
2006-09-08
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$1,521,168
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Martinez-Garay, Isabel; Gil-Sanz, Cristina; Franco, Santos J et al. (2016) Cadherin 2/4 signaling via PTP1B and catenins is crucial for nucleokinesis during radial neuronal migration in the neocortex. Development 143:2121-34
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Barros, Claudia S; Franco, Santos J; Müller, Ulrich (2011) Extracellular matrix: functions in the nervous system. Cold Spring Harb Perspect Biol 3:a005108
Franco, Santos J; Müller, Ulrich (2011) Extracellular matrix functions during neuronal migration and lamination in the mammalian central nervous system. Dev Neurobiol 71:889-900

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