Cortical development is critical to proper brain function in children and adults, but the mechanisms underlying the regulation of neurogenesis and cell fate remain poorly understood at the molecular level. Understanding the mechanisms patterning neuronal connections is essential to understanding their roles in nervous system function and dysfunction. This proposal aims to identify a critical molecular mechanism specifying the timing of cell differentiation and post-mitotic characteristics in the developing neocortex. We have previously undertaken studies to identify genes controlling polarity during cortical development and established LKB1 (also called Par4), a serine-threonine kinase, as a key regulator of both axon-dendrite polarity and cell survival. We now focus on the regulation of LKB1 by the pseudokinase STRAD-alpha. Human patients lacking STRAD-alpha suffer from a Polyhydramnios, Megalencephaly and Symptomatic Epilepsy (PMSE) syndrome. It is characterized by severe infantile-onset epilepsy of unknown origin. Our key hypothesis in this application is that: STRAD-alpha significantly contributes to brain development by contributing to multiple aspects of progenitor differentiation and post-mitotic characteristics of the developin cortex in part by uniquely altering LKB1 activity and stability. In this application, we propose to understand 1.) the prenatal and 2.) post-natal impact of STRAD-alpha loss in a murine model of cortical development. We will also 3.) pursue the regulation of LKB1 by STRAD-alpha and understand how this contributes to overall regulation of LKB1 activity. We will then use both gain- and loss-of-function approaches both in vitro and in vivo to determine how STRAD- alpha contributes to LKB1 function in the developing brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079433-01
Application #
8343134
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$336,875
Indirect Cost
$118,125
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Veleva-Rotse, Biliana O; Smart, James L; Baas, Annette F et al. (2014) STRAD pseudokinases regulate axogenesis and LKB1 stability. Neural Dev 9:5
Cho, Hyong-Ho; Cargnin, Francesca; Kim, Yujin et al. (2014) Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. PLoS Genet 10:e1004280
Veleva-Rotse, Biliana O; Barnes, Anthony P (2014) Brain patterning perturbations following PTEN loss. Front Mol Neurosci 7:35