Transcription factor Pax6 protects mouse cortical cell fate specification

The mammalian cortex is composed of two main types of neuron. Principal cells (PCs) are glutamatergic and use glutamate as the main neurotransmitter. Interneurons are mostly GABAergic and use GABA as their main neurotransmitter. PCs are the output units of the cortex and comprise ~80-85% of the mouse cortex. Interneurons modulate the activity of PCs and comprise ~20-15% of the mouse cortex. These two broad cell types originate from separate regions of the developing nervous system. Early embryo development is dependent on the balance between cell proliferation and differentiation. The process of cortical progenitor pool expansion, division and production of postmitotic cells starts at around embryonic day (E) 10.5. PCs arise from the dorsal telencephalon while interneurons arise from the ventral telencephalon. The process of telencephalon regionalization is regulated by differential expression of transcription factors (TFs). Pax6 is one of such TFs. Importantly, it is expressed strongly in the PC dorsal Emx1 lineage but much less so or not at all in interneuron ventral lineages. Here I investigated the postnatal characteristics of a Cre-loxP recombinant mouse that had Pax6 removed from the Emx1-lineage at E11.5. I targeted L5 and L2/3 of the somatosensory cortex and recorded their intrinsic electrophysiological properties. The results suggested that PCs can be specified without the need for Pax6 as the intrinsic properties of neurons in layers 5 and layers 2 and 3 were not significantly different than those of control cells. I explored an ectopic population of cells from the Emx1-lineage that expressed GABAergic markers in the embryo using electrophysiology and immunostaining. The results indicated that ectopic cells do not develop much electrical activity and stay in a state of arrested development. I investigated the consequences of deleting Pax6 in Emx1-lineage progenitor cell cultures. The results revealed the possibility that Emx1-lineage progenitors can produce interneurons in the absence of Pax6 if Sonic Hedgehog is activated. Taken together, the results support the hypothesis that Pax6 protects cortical PC specification by inhibiting interneuron-inducing signals.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2022

Author dc:creator

• Marcos, Tiago S.

Advisors dc:contributor.advisor

• Daw, Michael
• Price, David
• Manuel, Martine
• Stefan, Melanie

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/2463

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/39212