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

Abstract

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.

Hepatic Autonomic Nervous System and Neurotrophic Factors Regulate the Pathogenesis and Progression of Non-alcoholic Fatty Liver Disease

“…NRG4 is a neurotrophic factor that belongs to Neuregulin family of epidermal growth factor-like ligands and signals through tyrosinase kinase receptor members of the ErbB family (89). It regulates neuron development, adipocyte differentiation, brown adipose tissue thermogenesis, and energy homeostasis (90)(91)(92). It is also produced in both brown and white adipose tissues and then transduces signal to hepatocytes in an endocrine fashion through ErbB4 receptors.…”

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity

“…Different from the other NRGs, NRG4 expression appears more confined to peripheral organs, being expressed at high levels in the pancreas, in the skeletal muscle, and in the brown adipose tissue, with its expression in adult brain considered negligible [27,29]. Recently, however, NRG4 expression has been reported in the developing brain, in various brain areas like cortex, hippocampus, cerebellum, olfactory bulb, midbrain, and brain stem [30].…”

“…This questions the postsynaptic/cell autonomous function of ErbB4 in the NRGs-dependent LTP impairment at CA3-CA1 synapses. Notwithstanding, in spite of undetected expression, ErbB4 functions in hippocampal and cortical pyramidal neurons have been reported [30,72,[83][84][85][86]. Thus, the factual role of ErbB4 in hippocampal CA1 pyramidal cells in NRGs-dependent LTP regulation remains to be better elucidated.…”

Neuregulin and ErbB expression is regulated by development and sensory experience in mouse visual cortex

“…NRG3 is expressed very strongly throughout the cortex during development and adulthood (Anton et al, ; Bartolini et al, ; Li, Chou, Hamasaki, Perez‐Garcia, & O'Leary, ; Longart, Liu, Karavanova, & Buonanno, ; Loos et al, ; Rahman, Weber, Labin, Lai, & Prieto, ; Zhang et al, ). Alternatively, NRG2 and NRG4 are present in adult cortex, but not at very high levels (Anton et al, ; Longart et al, ; Paramo, Wyatt, & Davies, ; Yan et al, ). NRG3 is a ligand for ErbB4 but has a lower affinity for ErbB4 than does NRG1 (Hobbs et al, ; Jones, Akita, & Sliwkowski, ; Zhang et al, ).…”