Notch1 and Notch2 collaboratively maintain radial glial cells in mouse neurogenesis

Area of Science:

• Developmental Neuroscience
• Cell Biology
• Genetics

Background:

• Notch signaling is critical for mammalian corticogenesis, maintaining neural stem cells (radial glial cells, RGCs) and cortical structure.
• The specific roles and interplay of Notch1 and Notch2 in RGC maintenance during corticogenesis remain unclear due to early neuroepithelial loss in conventional knockouts.

Purpose of the Study:

• To elucidate the distinct and cooperative functions of Notch1 and Notch2 in regulating radial glial cells during mouse corticogenesis.
• To investigate the impact of single and combined genetic ablation of Notch1 and Notch2 on RGC maintenance and neurogenesis.

Main Methods:

• Utilized single gene knockouts for Notch1 and Notch2 in mice.
• Performed conditional double knockout (DKO) of Notch1 and Notch2 specifically in RGCs.
• Analyzed the effects on RGC pool size, maintenance, and neurogenesis throughout corticogenesis.

Main Results:

• Notch1 single knockout impaired RGC maintenance during early to mid-neurogenesis.
• Notch2 single knockout showed no significant defect, but Notch2 contributed to RGC maintenance at later stages.
• Notch1 and Notch2 DKO led to a complete depletion of RGCs, indicating functional cooperation.
• Notch activity in RGCs was dependent on gene dosage, with Notch1 and Notch2 exhibiting similar functions late in neurogenesis, potentially due to increased Notch2 transcription.

Conclusions:

• Notch1 plays an essential role in establishing the RGC pool during early corticogenesis.
• Notch1 and Notch2 exhibit overlapping and cooperative functions in maintaining RGCs and driving neurogenesis during the late neurogenic period.
• These findings reveal a dynamic and dosage-dependent role for Notch1 and Notch2 in regulating the critical processes of mammalian brain development.