Research

AMH is a conserved regulator of reproductive development. In the male fetus, AMH secreted by Sertoli cells drives regression of the Müllerian ducts. In the female, AMH produced by granulosa cells acts as a negative regulator of folliculogenesis, limiting recruitment of primordial follicles. Both functions depend on a signaling mechanism that remained incompletely defined, and on a prodomain whose structure was unknown.

Structure of the AMH procomplex

Prodomain behavior varies across the TGF-β family. Some ligands, including TGF-β1 and GDF8, are held in a latent state requiring subsequent activation, while others use the prodomain primarily as an allosteric regulator of receptor binding. High-affinity prodomain interactions are typically associated with latency. AMH is an exception: its prodomain binds with high affinity and remains associated until displaced by bivalent receptor engagement, yet the complex is non-latent and the prodomain is obligatory for full bioactivity in vivo. We determined the first cryo-EM structure of the AMH prodomain and identified a two-domain architecture distinct from all other family members: a helical binding domain that engages the growth factor through an interface not used by other prodomains, tethered to a vestigial TGF-β propeptide domain that mediates dimerization. These studies also resolved the growth factor in a distinct conformational state, supporting a two-step displacement mechanism in which AMHR2 engagement induces a conformational shift that precedes prodomain release. Published in PNAS (2025).

Engineering AMH for therapeutic use

Native AMH is poorly suited to therapeutic development. Full bioactivity requires the intact procomplex rather than the mature growth factor alone, and that form is difficult to produce with acceptable yield and homogeneity and difficult to characterize once administered. Guided by the structure of the procomplex, I design variants intended to improve these properties without compromising signaling activity.

Contraception, oncofertility, and IVF

Temporary supraphysiological activation of AMH signaling induces a reversible quiescent state in the ovary without significant follicular atresia or depletion of the ovarian reserve. The Pépin Lab has established this in the domestic cat: a single intramuscular dose of an AAV-delivered feline AMH transgene produced durable contraception for at least two years (Vansandt et al., Nature Communications, 2023), and the same approach in prepubertal animals induced long-term sterilization (Godin et al., Nature Communications, 2025). In rodents, cessation of treatment restores coordinated follicle development. These properties support three applications: nonhormonal contraception, fertility preservation during chemotherapy, and control of follicle recruitment in IVF. The principal constraints are dose and molecular form. The therapeutic window appears narrow, and chronic supraphysiological signaling has produced adverse endocrine effects in animal models, so defining the active molecular species and its circulating concentration remains central to translation.

Approach

My work combines structural characterization with functional validation. Projects typically pair cryo-EM or crystallography with cell-based signaling assays and, where appropriate, in vivo studies conducted with collaborators. Difficult targets are more often resolved through construct design and expression optimization than through additional data collection. More recently this has extended to computational protein design, applying structure prediction and de novo methods to generate binders and agonists of the pathway.