An essential role for neuregulin-4 in the growth and elaboration of developing neocortical pyramidal dendrites

Neuregulins, with the exception of neuregulin-4 (NRG4), have been shown to be extensively involved in many aspects of neural development and function and are implicated in several neurological disorders, including schizophrenia, depression and bipolar disorder. Here we provide the first evidence that NRG4 has a crucial function in the developing brain. We show that both the apical and basal dendrites of neocortical pyramidal neurons are markedly stunted in Nrg4^-/- neonates in vivo compared with Nrg4^+/+ littermates. Neocortical pyramidal neurons cultured from Nrg4^-/- embryos had significantly shorter and less branched neurites than those cultured from Nrg4^+/+ littermates. Recombinant NRG4 rescued the stunted phenotype of embryonic neocortical pyramidal neurons cultured from Nrg4^-/- mice. The majority of cultured wild type embryonic cortical pyramidal neurons co-expressed NRG4 and its receptor ErbB4. The difference between neocortical pyramidal dendrites of Nrg4^-/- and Nrg4^+/+ mice was less pronounced, though still significant, in juvenile mice. However, by adult stages, the pyramidal dendrite arbors of Nrg4^-/- and Nrg4^+/+ mice were similar, suggesting that compensatory changes in Nrg4^-/- mice occur with age. Our findings show that NRG4 is a major novel regulator of dendritic arborisation in the developing cerebral cortex and suggest that it exerts its effects by an autocrine/paracrine mechanism.