EphA7 signaling guides cortical dendritic development and spine maturation

Abstract

The process by which excitatory neurons are generated and mature during the development of the cerebral cortex occurs in a stereotyped manner; coordinated neuronal birth, migration, and differentiation during embryonic and early postnatal life are prerequisites for selective synaptic connections that mediate meaningful neurotransmission in maturity. Normal cortical function depends upon the proper elaboration of neurons, including the initial extension of cellular processes that lead to the formation of axons and dendrites and the subsequent maturation of synapses. Here, we examine the role of cell-based signaling via the receptor tyrosine kinase EphA7 in guiding the extension and maturation of cortical dendrites. EphA7, localized to dendritic shafts and spines of pyramidal cells, is uniquely expressed during cortical neuronal development. On patterned substrates, EphA7 signaling restricts dendritic extent, with Src and Tsc1 serving as downstream mediators. Perturbation of EphA7 signaling in vitro and in vivo alters dendritic elaboration: Dendrites are longer and more complex when EphA7 is absent and are shorter and simpler when EphA7 is ectopically expressed. Later in neuronal maturation, EphA7 influences protrusions from dendritic shafts and the assembling of synaptic components. Indeed, synaptic function relies on EphA7; the electrophysiological maturation of pyramidal neurons is delayed in cultures lacking EphA7, indicating that EphA7 enhances synaptic function. These results provide evidence of roles for Eph signaling, first in limiting the elaboration of cortical neuronal dendrites and then in coordinating the maturation and function of synapses.dendritic spine | neurogenesis | synaptogenesis

Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation

“…These findings demonstrate that vitamin C activation of Tet enzymes, which increased levels of 5hmC, result in up-regulation of genes involved in axon guidance, as well as ion channel genes involved in neuronal conductance and activity. Importantly a large number of studies demonstrate that axon guidance genes, including many of those found in our analyses, also function in dendrite outgrowth (Clifford et al, 2014; Polleux et al, 2000; Whitford et al, 2002), thus playing critical roles in the establishment of neuronal circuitry.…”

“…These findings are consistent with other recent studies showing that Tet3 gene overexpression disrupts axon targeting in the developing olfactory system (Colquitt et al, 2013) and that Tet1 has important functions in memory formation (Kaas et al, 2013) and neuronal activity-related gene expression in memory extinction (Rudenko et al, 2013). In addition, a large number of studies demonstrate that axon guidance genes, including many of those found in our analyses, also function in dendrite outgrowth (Clifford et al, 2014; Polleux et al, 2000; Whitford et al, 2002), thus playing critical roles in the establishment of neuronal circuitry. Taken together, these studies underscore the importance of Tet genes to CNS circuit formation and function.…”

Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications

“…Regulations through Ephrin receptors have been shown to guide axon elongation of neuronal cells [51], [52] and their suppression in certain contexts promotes tumorigenesis [53]. Remarkably, Eph A4 loss has been shown to promote axon regeneration [54], [55], Eph A7 suppression has been shown to help complex dendrite formations and axon elongation [56]. Taken together, they suggest the involvement of the Wnt signaling pathway and provide additional support to the differentiation of PCa cells to neuron-like cells with highly complex neurite-like processes.…”

Regulation of dendrite morphogenesis by extrinsic cues

“…Among the EphA receptor proteins, EphA7 mediates the ability of the ligand ephrin-A5 to induce dendrite avoidance in cortical neurons via the signaling proteins Src and TSC1 [34]. Triple knockout of EphB1, EphB2, and EphB3 results in reduced dendrite number, length, and complexity in the mouse hippocampus [35], suggesting that EphB family receptors play key roles in dendrite development.…”