The growth factor EPIREGULIN promotes basal progenitor cell proliferation in the developing neocortex

Area of Science:

• Evolutionary biology
• Developmental neuroscience
• Genetics

Background:

• Neocortex expansion in evolution correlates with increased neuron numbers.
• This increase is linked to enhanced proliferative and neurogenic capacities of basal progenitor cells.
• The specific molecular mechanisms driving these changes remain incompletely understood.

Purpose of the Study:

• To investigate the role of Epiregulin (EREG) in neocortex development and evolution.
• To explore the species-specific regulation of EREG and its impact on basal progenitor cell proliferation.
• To understand the contribution of EREG to primate neocortex expansion.

Main Methods:

• Analysis of EREG expression in developing human neocortex and gorilla cerebral organoids.
• In vitro studies using mouse neocortex and human/gorilla cortical organoids.
• Manipulation of EREG expression (addition/ablation) and assessment of basal progenitor cell proliferation.
• Investigating the interaction between EPIREGULIN and the epidermal growth factor (EGF) receptor pathway.
• Identification of cis-regulatory elements potentially controlling EREG expression.

Main Results:

• EREG is expressed in human and gorilla neocortex but not mouse neocortex.
• EPIREGULIN enhances basal progenitor cell proliferation in mouse models.
• EREG ablation reduces proliferation in human cortical organoids.
• EPIREGULIN further increases proliferation in gorilla but not human organoids.
• EPIREGULIN competes with EGF for receptor binding, influencing proliferation.
• Putative cis-regulatory elements linked to inter-species differences in EREG expression were identified.

Conclusions:

• Species-specific regulation of EPIREGULIN expression is a key factor in primate neocortex expansion.
• EREG acts as a tunable pro-proliferative signal for basal progenitor cells in the subventricular zone.
• This mechanism contributes to the increased neocortex size observed in primates.