A Rapid Induction Mechanism for Lin28a in Trophic Responses

Area of Science:

• Molecular Biology
• Neuroscience
• Cellular Biology

Background:

• Environmental cues rapidly alter gene expression for growth and plasticity via unknown mechanisms.
• Lin28 RNA-binding proteins coordinate pro-growth gene expression, but upstream signaling remains unclear.

Purpose of the Study:

• To elucidate the signaling pathways that mediate trophic stimuli-induced Lin28 expression.
• To investigate the role of mitogen-activated protein kinase (MAPK) and TAR-RNA-binding protein (TRBP) in Lin28 regulation.

Main Methods:

• Investigated Lin28a protein turnover in neurons.
• Examined the effect of MAPK-dependent TRBP phosphorylation on Lin28a binding and stability.
• Assessed the impact on microRNAs (miRNAs) and neuronal dendritic spine growth.
• Studied TRBP and Lin28a induction by growth factors in primary cell types.

Main Results:

• Lin28a protein undergoes rapid turnover in neurons.
• MAPK-dependent phosphorylation of TRBP enhances binding and stabilizes Lin28a, reducing Lin28-regulated miRNAs downstream of BDNF.
• Phospho-mimic TRBP enhances Lin28a binding in vitro and recapitulates BDNF-induced neuronal growth.
• MAPK-dependent TRBP and Lin28a induction occurs downstream of various growth factors, impacting cell growth and survival.

Conclusions:

• A novel pathway involving MAPK-dependent TRBP phosphorylation stabilizes Lin28a, mediating trophic factor-induced cellular growth and survival.
• This mechanism plays a broad role in cellular trophic responses across multiple cell types.
• Findings uncover a key regulatory mechanism for Lin28a in response to growth signals.