ASCL1 promotes nuclear shrinkage in transdifferentiation by suppressing NUP37.

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• Nuclear size is crucial for cellular function but poorly understood.
• A correlation between nuclear and cell size exists, but exceptions like neurons challenge this.
• Understanding nuclear size regulation is key to cell state determination.

Purpose of the Study:

• To investigate the mechanisms controlling nuclear size during cell reprogramming.
• To identify factors influencing nuclear size reduction in induced neurons.

Main Methods:

• Direct conversion of human fibroblasts to induced neurons using ASCL1, miR124-9-9*, and p53 shRNA (AMp).
• Analysis of nuclear and cell size changes during transdifferentiation.
• Investigating the role of ASCL1 and nucleoporin NUP37 in nuclear size regulation via promoter binding and knockdown/overexpression studies.

Main Results:

• AMp treatment induced significant nuclear size reduction without affecting cell size in fibroblasts.
• ASCL1 directly suppressed NUP37 transcription.
• NUP37 knockdown promoted AMp-mediated nuclear shrinkage, while NUP37 overexpression inhibited it.

Conclusions:

• ASCL1-mediated suppression of NUP37 is a critical mechanism for nuclear shrinkage during induced neuron formation.
• Nuclear pore complex (NPC) size and function are implicated in regulating nuclear size to match cellular state.
• This study provides insights into how nuclear size is dynamically controlled during cell differentiation and reprogramming.