Neuropathological signatures revealed by transcriptomic and proteomic analysis in Pten-deficient mouse models

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• PTEN hamartoma tumour syndrome arises from mutations in the PTEN gene.
• Understanding PTEN's role in neural development is crucial for comprehending associated disorders.

Purpose of the Study:

• To investigate the molecular and cellular consequences of PTEN gene mutations in neural tissues.
• To identify specific pathways and functions affected by Pten deficiency in the brain.

Main Methods:

• Transcriptomic and proteomic analyses were conducted on neural tissues and primary cultures from Pten-knockout mice (heterozygous and homozygous).
• Gene Ontology (GO) term enrichment analysis and differential protein expression (DEP) analysis were performed.

Main Results:

• Heterozygous Pten-knockout mice showed altered immune response and oligodendrocyte development in the somatosensory cortex.
• Primary astrocytes (ASTs) and cortical neurons (PCNs) displayed distinct molecular changes, including extracellular matrix enrichment in ASTs and immediate-early gene enrichment in PCNs.
• Homozygous Pten-knockout mice exhibited cilium-related activity changes in ASTs and impaired neuron generation/differentiation in PCNs, suggesting an altered excitatory/inhibitory balance.
• Integrated analysis linked DEPs with intelligence, cognitive function, schizophrenia, and depression traits.

Conclusions:

• Pten deficiency significantly impacts diverse neural cell types, affecting fundamental processes from immune response to neuronal differentiation.
• The study reveals a molecular basis linking PTEN mutations to cognitive functions and psychiatric disorders, including intelligence, schizophrenia, and depression.