System-level analyses of keystone genes required for mammalian tooth development

Area of Science:

• Developmental Biology
• Genomics
• Evolutionary Biology

Background:

• Genes essential for life often cause complete developmental arrest, but many null mutations have subtle phenotypic effects.
• Understanding system-level gene expression dynamics can provide insights into gene function beyond simple essentiality.
• The mouse molar serves as a model system to study gene function during mammalian development.

Purpose of the Study:

• To investigate system-level dynamics of gene expression using the phenotypic severity of mutations.
• To classify genes involved in mouse molar development based on their phenotypic impact.
• To explore conserved system-level principles of gene expression across species.

Main Methods:

• Phenotypic classification of genes critical for mouse molar development into categories of essential to subtle effect.
• Transcriptome profiling using microarray and RNA sequencing (RNAseq) on mouse and rat molars.
• Single-cell RNA sequencing (scRNAseq) to analyze cell-level gene expression and domain size.

Main Results:

• Genes essential for tooth development progression exhibit highly elevated expression levels, similar to essential genes in single-cell organisms.
• This elevated expression of progression genes is conserved in developing rat molars, indicating evolutionary conservation.
• Progression genes display high cell-level transcript abundance and pathway upregulation, despite organ-level expression being driven by domain size.

Conclusions:

• Phenotypic severity of mutations can be used as a tool to uncover system-level gene expression dynamics.
• Conserved system-level principles of gene expression exist, even when individual gene expression patterns vary.
• Developmental keystone genes, particularly those essential for progression, exhibit distinct, conserved expression characteristics.