Investigating Zfhx3 function in the mouse brain: characterising dopamine-related behavioural and molecular functions

Thesis

Zinc finger homeobox 3 (Zfhx3) is a brain-region enriched transcription factor that binds to AT motifs in promoter and enhancer regions. Zfhx3 has been shown, using mouse models, to have an important role in transcriptional regulation of neuropeptides and their receptors within the suprachiasmatic nucleus (SCN), allowing for the maintenance of typical circadian rhythms. In humans, coding sequence mutations have been linked to a range of diseases, including schizophrenia.

In addition to the SCN, data from the Allen Brain Atlas show Zfhx3 expression within dopaminergic regions in the mouse midbrain. Given the dopaminergic hypothesis of schizophrenia, and the genetic associations, we wish to elucidate the contribution of Zfhx3 to schizophrenia-related behavioural changes in mice.

We established a DAT-Cre (dopamine active transporter) driven Zfhx3 knockout mouse – a conditional knockout mouse model which deletes Zfhx3 in dopaminergic cells only. We also generated a Zfhx3 knockout mouse cohort via injection of Cre-expressing adeno-associated virus (AAV) into the ventral tegmental area of Zfhx3-floxed mice – targeting the origin of key dopaminergic pathways.

These mice have been subject to a behavioural phenotype pipeline focused on schizophrenia-related endophenotypes, then sub-dissected midbrain and dopamine pathway terminus brain regions have undergone molecular analysis to investigate changes in gene expression.

We discuss the biological relevance of these findings, particularly in how they relate to dopaminergic function in physiology and disease.

Authors: Street, P

• DOI: 10.5287/ora-5zr8yqozk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Zfhx3; Zinc finger homeobox 3; schizophrenia
• Subjects: Behavior genetics