Cortical Interneurons are an incredibly diverse population of locally connecting GABAergic inhibitory neurons. In rodents, cortical interneurons originate from the ventral telencephalon during embryogenesis, and migrate tangentially into the neocortex following their specification. Despite our understanding of the early patterning of the telencephalon, established through sonic hedgehog (SHH), fibroblast growth factor (FGF) signaling, and wingless-int (WNT) we still know very little about the downstream effectors responsible for establishing interneuron diversity. This work has aimed to elucidate the role of secreted morphogens in interneuron specification, specifically FGF and WNT.
I began by investigating the role of FGF signaling in the specification of cortical interneurons by targeting downstream effectors, a critical adaptor protein, and receptors for FGF signaling. In particular, I examined the role of two candidate transcription factors classically found downstream of FGF: Ets1 and Ets2. Previously identified by microarray as enriched in cortical interneurons at developmental timepoints, Ets1 and Ets2 single and double mutants had no obvious defects in interneuron specification as assessed by immunohistochemistry. Using both forebrain and interneuron specific Cre recombinase drivers, I also generated conditional knockouts of the adaptor protein FRS2α, which is critical for FGF signaling through the MAP kinase and PI3 kinase signaling pathways (Hadari et al, 2001). Interestingly, pan-forebrain loss of FRS2α, failed to replicate the phenotype of forebrain removal of FGF receptors 1, 2 and 3. Similarly, interneuron specific removal of FRS2α, did not affect interneuron migration or fate. Additionally, through a complex set of genetic crosses, I generated an interneuron specific triple knockout of FGFRs 1, 2, and 3; this animal also did not exhibit any gross interneuron specification defects. These results together suggest that the development of cortical interneurons is likely not regulated by FGF signaling, at least not after their initial specification.
Previous work in the developing spinal cord has shown that cell identity can be conferred by exposure to diffusible morphogen gradients. Despite previous attempts, delineation of cell types by morphogen gradient in a "spinal cord" fashion has not yet been discovered in the forebrain. We have discovered a novel rostral-caudal regionality within the medial ganglionic eminence (MGE) that delineates the specification of the two main classes of cortical interneuron subtypes based on their exposure to a non-canonical WNT signaling gradient. Caudally located MGE progenitors receiving high levels of WNT signaling give rise to cortical interneurons labeled by somatostatin (SST). Parvalbumin (PV) expressing basket cells, in contrast, originate primarily from the most rostral region of the MGE, and do not signal highly through WNT pathways. Interestingly, canonical WNT signaling through β-catenin is not required for this process. WNT signals transmitted via cleavage of the intracellular domain of the non-canonical WNT receptor RYK, however, are sufficient to drive interneuron progenitors to a SST fate.
|Commitee:||Cepko, Constance, Dasen, Jeremy, Desplan, Claude, Mohammadi, Moosa|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 76/04(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Developmental biology|
|Keywords:||Forebrain, Interneurons, MGE, Patterning, Specification, WNT|
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