Selector functions of Lhx2 during mouse cerebral cortex development.

摘要

Cerebral cortex development is a complex process, whereby an initially simple layer of neuroepithelial stem cells specializes and proliferates, ultimately leading to the formation of the structurally and functionally diverse mature cortex. Previous mouse genetic studies demonstrated that the LIM-homeodomain transcription factor, Lhx2 is required for proper cortical development, however inherent limitations of the genetic strategy used prevented determination of the mechanism of action.;I performed genetic mosaic analyses using an Lhx2 conditional knockout mouse to address the role of Lhx2 in the preneurogenic neuroepithelium. My results provide molecular, cellular, and functional evidence that Lhx2 is a cortical selector gene. I demonstrate that Lhx2 cell-autonomously specifies cortical identity, suppresses alternative fates, and confers differential cell affinity properties. Collectively, this results in the positioning of the Bmp (cortical hem) and Egf (antihem) secondary signaling centers to the edges of the dorsal telencephalon. Furthermore, I defined the period of Lhx2 selector activity as occurring between embryonic day 8.5 (E8.5) and E10.5, a time where the dorsal forebrain is comprised nearly exclusively of neuroepithelial stem cells. Defining Lhx2 selector activity to this early time period situates Lhx2 near the top of the hierarchy of intrinsic determinants specifying cortical stem cell identity.;Though Lhx2 selector function is finished by E10.5, Lhx2 continues to be expressed in the cortical domain through later stages of embryonic development. By conditionally inactivating Lhx2 alter the period of selector activity, I examined the role of Lhx2 in correctly specified cortical radial glial cells (RGCs). My results indicate that Lhx2 maintains RGCs in an undifferentiated state by delaying the onset of neurogenesis and astrogliogenesis. Furthermore, I provide evidence that Lhx2 suppression of astrogliogenic cell types occurs through the suppression of responsivity to the astrogenic cytokines, Bmp4 and Egf. My results thus demonstrate a common property of Lhx2 is to mediate the effects of Bmp and Egf on cortical development. Specifically, Lhx2 possesses an early role in suppressing the specification of Bmp and Egf producing cells (preneurogenic selector function), and a latter role in suppressing responsivity of RGCs to the astrogliogenic influences of Bmp4 and Egf signaling (astrogliogenic selector function).