Matrix metalloproteinase-3 (MMP-3) deficiency in mice was previously reported to result in a transiently retarded granule cell migration at postnatal day 8 (P8) and a sustained disturbed arborization of Purkinje cell dendrites from P8 on, concomitant with a delayed synapse formation between granule cells and Purkinje cells and resulting in mild deficits in motor performance in adult animals. However, the molecular mechanisms by which MMP-3 contributes to proper development of the cerebellar cortex during the first postnatal weeks remains unknown. In this study, we used a functional proteomics approach to investigate alterations in protein expression in postnatal cerebella of wild-type versus MMP-3 deficient mice, and to further elucidate MMP-3-dependent pathways and downstream targets in vivo. At P8, two-dimensional difference gel electrophoresis (2-D DIGE) and mass spectrometry identified 20 unique proteins with a different expression between the two genotypes. Subsequent 'Ingenuity Pathway Analysis' and Western blotting indicate that the chaperonin containing T-complex polypeptide 1, subunit 6A (CCT6a) and the MAP kinase signaling pathway play a key role in the MMP-3-dependent regulation of neurite outgrowth and neuronal migration in the developing brain.