Transcriptional control of the establishment of neocortical projections in the mammalian telencephalon

by Swathi Srivatsa
Doctoral thesis
Date of Examination:2014-06-17
Date of issue:2015-01-12
Advisor:Prof. Dr. Victor Tarabykin
Referee:Dr. Judith Stegmüller
Referee:Prof. Dr. André Fischer
Persistent Address: http://dx.doi.org/10.53846/goediss-4855

 

 

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Abstract

English

Neuronal connections in the neocortex that relay and integrate informationform the basis of our higher cognitive abilities. Transcription factors play animportant role in controlling the trajectory of neuronal projections. They actas molecular switches capable of modulating downstream targets that in turnalter growth cone behavior. In this study we have investigated the role ofthree different transcription factors, namely Sip1, Satb2 and Ctip2 and theirdownstream mechanisms that influence the establishment of neocorticalprojections.Sip1 is an important transcription factor that regulates many different aspectsof CNS development. We show that, Sip1 also plays an important role in thedevelopment of neocortical projections. In the absence of Sip1 from theneocortex, many axonal tracts within the forebrain are severely affected.While the commissural projections like the corpus callosum (CC) and anteriorcommissure are not formed in the Sip1 mutant, corticofugal connections likethe cortico-spinal tract is also affected.Sip1 exerts both cell autonomous as well as non-cell autonomous control over CC formation. The non-cell autonomous effects of Sip1 deletion alter thecortical midline, making it unfavorable for commissural axons to cross.Fusion of the dorsal midline does not occur, different populations of GFAPpositive midline glia are either reduced or absent and subcallosal slingneurons are mislocalized. Cell autonomous deletion of Sip1 also results in the lack of corpus callosumformation and lack of ipsilateral axon-collateral formation. Sip1 mediatesthese effects through its direct downstream effector ninein, a microtubulebinding protein. We further show that ninein in turn influences axon growthand branching by affecting microtubule stability and dynamics.2The transcription factors Satb2 and Ctip2, are critical regulators of neuronalcell fate that control commissural versus corticofugal projections respectively.In this study, we have investigated the axon guidance molecules downstreamof Satb2 and Ctip2 that govern the trajectory choice made by neocorticalneurons. We show that Satb2 and Ctip2 transcriptionally regulate theexpression of two Netrin1 receptors - DCC and Unc5C respectively. Withindeep layer neurons, Netrin1- Unc5C/DCC interactions are involved incontrolling the commissural versus corticofugal trajectory choice made bythese axons.
Keywords: Neuroscience; cortical development; cortical projections; corpus callosum; corticospinal tract
 
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