The homeodomain has a modulating role on Pax6 function in the endocrine pancreas. Two mutant mouse lines, Pax64Neuand Pax614Neu, in which point mutations in the third helix of the homeodomain abolish binding the P3 homeodomain consensus DNA sequence were studied. Although neighboring amino acids are affected in the two mutants Pax64Neu homozygotes die shortly after birth while Pax614Neu mutants live to adulthood. A. In e18.5 Pax64Neu homozygotes both α- and β-cells are reduced to 59 and 61 percent, respectively (6-7 animals/group; *p < 0,05). The ratio of α- to β-cells is unchanged. B-E. In 6 week old Pax614Neu homozygotes islet architecture is unchanged compared to wt. F. Islet- and α-cell area comparable in wt and Pax614Neu mutants (3 mice/group).