Desmosomes are cell-cell adhesion structures that integrate cytoskeletal 
networks. In addition to binding intermediate filaments, the desmosomal protein 
desmoplakin (DP) regulates microtubule reorganization in the epidermis. In this 
paper, we identify a specific subset of centrosomal proteins that are recruited 
to the cell cortex by DP upon epidermal differentiation. These include Lis1 and 
Ndel1, which are centrosomal proteins that regulate microtubule organization and 
anchoring in other cell types. This recruitment was mediated by a region of DP 
specific to a single isoform, DPI. Furthermore, we demonstrate that the 
epidermal-specific loss of Lis1 results in dramatic defects in microtubule 
reorganization. Lis1 ablation also causes desmosomal defects, characterized by 
decreased levels of desmosomal components, decreased attachment of keratin 
filaments, and increased turnover of desmosomal proteins at the cell cortex. 
This contributes to loss of epidermal barrier activity, resulting in completely 
penetrant perinatal lethality. This work reveals essential desmosome-associated 
components that control cortical microtubule organization and unexpected roles 
for centrosomal proteins in epidermal function.