Removal of Pax6 from cortical progenitors renders them abnormally likely to switch fate in response to Sonic Hedgehog activity

The paired-box protein PAX6 is a transcription factor that acts as a master regulator during neurodevelopment. In mice, it is expressed by neural progenitors in the cortical ventricular zone (VZ) where it regulates neurogenesis and fate specification. The complex processes of neurodevelopment are also regulated by morphogens such as Sonic Hedgehog (Shh) that promotes ventralization of the ventral telencephalon (vTel), through diffusion to form a concentration gradient. Strikingly, when Pax6 is deleted, a subset of cortical progenitor cells that would normally become glutamatergic commit into a GABAergic fate, expressing ventral markers such as Gad67, Gsx2 and Dlx1. Previous studies have shown that when wild-type cortical cells are treated with substances that activates Shh signalling, they can be made to express genes such as Gsx2 which are associated with the generation of interneurons. Based on these findings, we asked what makes cortical progenitor cells change their fate when Pax6 is deleted? This study aimed to investigate the sensitivity of cortical progenitor cells in Pax6 mutant mice to Shh signalling. In the present study, we used Pax6-floxed (Pax6fl/fl) mutant mice expressing a tamoxifen-inducible form of Cre recombinase under the control of the Emx1 locus (Emx1-CreERT2) and an EGFP reporter construct. Cultured cortical progenitors were exposed to increasing concentrations of Shh agonist, developed for the protein Smoothened (SAG), which is a key part of the activation of Hedgehog signalling pathway. Results showed significant increases of Gsx2+, Dlx1+ Olig2+ cells in parallel with the increase of Shh agonist concentrations. We also investigated the possibility that these cells matured into interneurons (INs) after exposure to SAG, if they do have electrical properties akin to specific type of INs. Our finding suggests that morphogens such as Shh exert a ventralizing effect on cortical progenitors, and Pax6 is required to resist such an effect in order to safeguard glutamatergic fate. These cells also have the potential to develop into a subtype of IN when exposed to SAG.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2023

Author dc:creator

• Abd Razak, Maizatul Fazilah

Advisors dc:contributor.advisor

• Johnstone, Mandy
• Mason, John
• Chan, Wai Kit
• Price, David

• Pax6
• cortical progenitors
• Removal of Pax6
• Sonic Hedgehog
• neurodevelopment
• cortical ventricular zone
• neurogenesis
• fate specification
• morphogens
• ventral telencephalon
• concentration gradient
• glutamatergic
• GABAergic fate
• ventral markers
• Shh signalling
• Gsx2
• tamoxifen-inducible
• Cre recombinase
• Smoothened
• SAG

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/3158

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/40390