Modelling a pathological GSX2 variant that selectively alters DNA binding reveals hypomorphic mouse brain defects

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Gsx2 is a critical homeodomain transcription factor for ventral telencephalon and hindbrain development in mice.
• Loss of Gsx2 function leads to severe basal ganglia dysgenesis, nucleus tractus solitarius (nTS) defects, and respiratory failure.
• Human patients with recessive GSX2 variants exhibit dystonia and basal ganglia dysgenesis.

Purpose of the Study:

• To investigate the functional impact of a specific Gsx2 homeodomain missense variant (GSX2Q252R) on brain development and survival.
• To compare the phenotypic effects of the Gsx2Q252R variant with Gsx2 null mutations.

Main Methods:

• Modeled the homologous Gsx2 mutation (Gsx2Q252R) in mice.
• Performed biochemical analysis to assess DNA binding alterations.
• Analyzed basal ganglia and hindbrain development in Gsx2Q252R mice.

Main Results:

• The Gsx2Q252R variant selectively altered DNA binding.
• Mice with the Gsx2Q252R allele showed basal ganglia dysgenesis, but less severe than Gsx2 null mice.
• Gsx2Q252R mice survived, with relative sparing of nTS neurons and catecholaminergic groups in the hindbrain.

Conclusions:

• The Gsx2Q252R variant acts as a hypomorph, affecting a subset of Gsx2-dependent neuronal subtypes.
• Distinct thresholds of catecholaminergic and/or glutamatergic nTS neurons are critical for survival.