What is the role of recepter dimerization in androgen action?

Mutations in the androgen receptor found in androgen insensitivity syndrome (AIS) patients provide a wealth of information on the molecular biology of this receptor. Most recently, we described how the ligand-binding domain of the androgen receptor dimerises. The importance of this dimerization is illustrated by the fact that many mutations which are correlated with AIS are predicted to disrupt this interface. To study this further, we will first develop a mouse model mimicking a dimerization mutation found in two siblings with AIS. In vitro, this mutation indeed disrupts dimerization without affecting ligand binding or receptor stability. The main question here is where the phenotype of this mouse model fits in the AIS spectrum between mild male infertility and complete AIS. During my PhD, I will also determine the effect of the dimer mutations on the transactivation process in cellular models by the state-of-the-art methodologies STARR-seq and CRISPR/Cas9. This will help identify the contribution of receptor dimerization in the transcription activation process. In the long run, a more detailed knowledge on androgen receptor functioning can guide the development of therapeutic strategies that inhibit or activate the androgen receptor in much more selective ways.