FOXG1 Research Foundation is providing rolling grants to scientists to understand the biology of FOXG1 with the ultimate goal of identifying innovative therapeutic strategies.


Functional/regulatory elements in FOXG1

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  • All pathogenic missense mutations thought to occur in the forkhead DNA binding domain

  • Deletions including cis-acting regulatory elements but not coding region result in a FOXG1 syndrome phenotype 

 

FOXG1 and brain development

DEVELOPMENT OF THE TELENCEPHALON:

  • FOXG1 is required for patterning the developing telencephalon, particularly for ‘ventral identity’ – ‘ventral’ denotes a region of the developing telencephalon that will become the basal ganglion

  • The pattern of FOXG1 expression in the developing telencephalon is a gradient – an abnormal ‘ventral’ region leads to corresponding defects in the opposite ‘dorsal’ region

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  • Mice engineered to lack FOXG1 expression show gross malformations of the cerebral cortex, with a smaller, irregularly shaped cortex, and nearly absent ventral telencephalon

NEUROGENESIS AND CELL PROLIFERATION:

  • FOXG1 plays a role in the timing of neurogenesis and patterning of the cerebral cortex:

    • FOXG1 suppresses early-neuronal cell types – allows for switch to neurons that reside in deeper layers of the cerebral cortex

  • Several publications support a role for Foxg1 in improving survival of neuronal progenitor cells (early cell types that give rise to neurons)

    • Some evidence to suggest that this does NOT require the DNA-binding activity of FOXG1

    • Possible avenue to explore genotype-phenotype correlations


Unlocking the mysteries of common neurodevelopmental disorders via FOXG1

AUTISM SPECTRUM DISORDERS: PROPORTION MONOGENIC – 15-34%

  • FOXG1 variant identified in an individual with ASD and his similarly affected mother

  • FOXG1 gene dose associated with ASD diagnosis

SCHIZOPHRENIA: PROPORTION MONOGENIC HERITABILITY 70-80%

  • A schizophrenia-associated loci was shown to physically interact with and regulate FOXG1 expression

  • Expression of schizophrenia-associated gene, GRID1, found to be significantly elevated in FOXG1 patient-derived iPSC neurons and Foxg1+/- fetal mouse brain

  • Epilepsy: Proportion Monogenic - – >40% in Epileptic Encephalopathies

  • ~87% of individuals with a FOXG1 mutation are diagnosed with epilepsy

  • Age of onset, seizure type, response to medication variable