Hoxa3 and Pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis

The thymus and parathyroid glands in mice develop from a thymus/parathyroid primordium that forms from the endoderm of the third pharyngeal pouch. We investigated the molecular mechanisms that promote this unique process in w hich two distinct organs form from a single primordium, using mice mutant f or Hoxa3 and Pax1. Thymic ectopia in Hoxa3(+/-)Pax1(-/-)compound mutants is due to delayed separation of the thymus/parathyroid primordium from the ph arynx. The primordium is hypoplastic at its formation, and has increased le vels of apoptosis. The developing third pouch in Hoxa3(+/-)Pax1(-/-) compou nd mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes. However, Gcm2 expression is reduced at E 11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pa x1(-/-) compound mutants. Subsequent to organ-specific differentiation from the shared primordium, both the parathyroids and thymus developed defects. Parathyroids in compound mutants were smaller at their formation, and abse nt at later stages. Parathyroids were also reduced in Pax1(-/-) mutants, re vealing a new function for Pax1 in parathyroid organogenesis. Thymic hypopl asia at later fetal stages in compound mutants was associated with increase d death and decreased proliferation of thymic epithelial cells. Our results suggest that a Hoxa3-Pax1 genetic pathway is required for both epithelial cell growth and differentiation throughout thymus and parathyroid organogen esis. (C) 2001 Academic Press.