Progenitor diversity is generated through a combination of cell-intrinsic and environmental mechanisms. Our work focuses on the role of the environment in controlling a transition in progenitors that occurs during late embryonic development in the cerebral cortex. As a result, a second progenitor population is generated which resides in a second germinal layer, the subventricular zone (SVZ). The transition from early/ventricular zone (VZ) progenitors to late/SVZ progenitors involves changes in phenotypic potential and in morphology. We have used functional assays in explant cultures of rodent cortex in combination with retroviral transduction in vitro and in vivo to identify several environmental signals that contribute to this transition: BMP4, FGF2, Shh, and Wnts 7a and 7b. These signals also have other functions in cortical progenitors, but our data indicate that their effect on progenitor maturation reflects a distinct threshold. Progenitors within the SVZ are heterogeneous, and we have focused on a subset of late/SVZ progenitors distinguished by expression of a high level of EGFRs. These cells are of particular interest for several reasons. The EGFR-hi subset is heterogeneous and includes multipotent stem cells. EGFR-hi cells have also been suggested as a source of gliomas. Understanding the mechanisms that control their development will therefore provide information that can be applied to both regenerative medicine and cancer biology. Our previous work generated a model that suggests that a balance between antagonistic extrinsic signals controls the development of the EGFR-hi subset of late/SVZ progenitors by establishing appropriate signaling thresholds. We will test this model in vivo in aim 1 using mutant mice in which the expression of components of candidate signaling pathways has been reduced or eliminated. We will focus on the EGFR-hi subset, but extend analysis to the SVZ generally, examining the impact of candidate signals on phenotypic and morphological changes associated with the VZ-SVZ transition. The contributions of candidate signals to the generation of diversity within the SVZ, particularly within the EGFR-hi subset, will be addressed in aim 2. Our previous work identified the serine-threonine kinase Akt-1 as a possible intracellular mediator of FGF2 on progenitor maturation and on the self-renewal of multipotent progenitors. The targets of Akt- 1 that mediate maturation and/or self-renewal will be addressed in aim 3.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS038306-05
Application #
6722552
Study Section
Special Emphasis Panel (ZRG1-SSS-P (01))
Program Officer
Owens, David F
Project Start
1999-12-17
Project End
2007-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
5
Fiscal Year
2004
Total Cost
$296,913
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sinor-Anderson, Amy; Lillien, Laura (2011) Akt1 interacts with epidermal growth factor receptors and hedgehog signaling to increase stem/transit amplifying cells in the embryonic mouse cortex. Dev Neurobiol 71:759-71
Lillien, Laura; Gulacsi, Alexandra (2006) Environmental signals elicit multiple responses in dorsal telencephalic progenitors by threshold-dependent mechanisms. Cereb Cortex 16 Suppl 1:i74-81
Sinor, Amy D; Lillien, Laura (2004) Akt-1 expression level regulates CNS precursors. J Neurosci 24:8531-41
Gulacsi, Alexandra; Lillien, Laura (2003) Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro. J Neurosci 23:9862-72
Viti, Jane; Feathers, Angela; Phillips, Jennifer et al. (2003) Epidermal growth factor receptors control competence to interpret leukemia inhibitory factor as an astrocyte inducer in developing cortex. J Neurosci 23:3385-93
Viti, Jane; Gulacsi, Alexandra; Lillien, Laura (2003) Wnt regulation of progenitor maturation in the cortex depends on Shh or fibroblast growth factor 2. J Neurosci 23:5919-27
Caric, D; Raphael, H; Viti, J et al. (2001) EGFRs mediate chemotactic migration in the developing telencephalon. Development 128:4203-16
Lillien, L; Raphael, H (2000) BMP and FGF regulate the development of EGF-responsive neural progenitor cells. Development 127:4993-5005