NEUROBEHAVIORAL DEFICITS IN MICE LACKING THE ERYTHROCYTE-MEMBRANE CYTOSKELETAL PROTEIN 4.1

The erythrocyte membrane cytoskeletal protein 4.1 (4.1R) is a structur al protein that confers stability and flexibility to erythrocytes via interactions with the cytoskeletal proteins spectrin and F-actin and w ith the band 3 and glycophorin C membrane proteins. Mutations in 4.1R can cause hereditary elliptocytosis, a disease characterized by a loss of the normal discoid morphology of erythrocytes, resulting in hemoly tic anemia [1], Different isoforms of the 4.1 protein have been identi fied in a wide variety of nonerythroid tissues by immunological method s [2-5]. The variation in molecular weight of these different 4.1 isof orms, which range from 30 to 210 kDa [6], has been attributed to compl ex alternative splicing of the 4.1R gene [7]. We recently identified t wo new 4.1 genes: one is generally expressed throughout the body (4.1G ) [8] and the other is expressed in central and peripheral neurons (4. 1N) [9]. Here, we examined 4.1R expression by in situ hybridization an alysis and found that 4.1R was selectively expressed in hematopoietic tissues and in specific neuronal populations, In the brain, high level s of 4.1R were discretely localized to granule cells in the cerebellum and dentate gyrus. We generated mice that lacked 4.1R expression; the se mice had deficits in movement, coordination, balance and learning, in addition to the predicted hematological abnormalities. The neurobeh avioral findings are consistent with the distribution of 4.1R in the b rain, suggesting that 4.1R performs specific functions in the central nervous system. (C) Current Biology Ltd ISSN 0960-9822.