Abstract
Neural stem/precursor cells (NPCs) generate the large variety of neuronal phenotypes comprising the adult brain. The high diversity and complexity of this organ have its origin in embryonic life, during which NPCs undergo symmetric and asymmetric divisions and then exit the cell cycle and differentiate to acquire neuronal identities. During these processes, coordinated regulation of cell cycle progression/exit and differentiation is essential for generation of the appropriate number of neurons and formation of the correct structural and functional neuronal circuits in the adult brain. Cend1 is a neuronal lineage-specific modulator involved in synchronization of cell cycle exit and differentiation of neuronal precursors. It is expressed all along the neuronal lineage, from neural stem/progenitor cells to mature neurons, and is associated with the dynamics of neuron-generating divisions. Functional studies showed that Cend1 has a critical role during neurogenesis in promoting cell cycle exit and neuronal differentiation. Mechanistically, Cend1 acts via the p53-dependent/Cyclin D1/pRb signaling pathway as well as via a p53-independent route involving a tripartite interaction with RanBPM and Dyrk1B. Upon Cend1 function, Notch1 signaling is suppressed and proneural genes such as Mash1 and Neurogenins 1/2 are induced. Due to its neurogenic activity, Cend1 is a promising candidate therapeutic gene for brain repair, while the Cend1 minimal promoter is a valuable tool for neuron-specific gene delivery in the CNS. Mice with Cend1 genetic ablation display increased NPC proliferation, decreased migration, and higher levels of apoptosis during development. As a result, they show in the adult brain deficits in a range of motor and nonmotor behaviors arising from irregularities in cerebellar cortex lamination and impaired Purkinje cell differentiation as well as a paucity in GABAergic interneurons of the cerebral cortex, hippocampus, and amygdala. Taken together, these studies highlight the necessity for Cend1 expression in the formation of a structurally and functionally normal brain.
Highlights
Neural stem and progenitor cells are the building blocks of the brain
Coexpression of Ran-binding protein M (RanBPM) with either Cend1 or Dyrk1B had a negative effect on Neuro2A cell differentiation in the presence of retinoic acid, as compared with cells expressing each protein separately. These results demonstrated that functional interactions between Cend1, RanBPM, and Dyrk1B influence the balance between cellular proliferation and differentiation in Neuro2A cells, suggesting that the three proteins may play a similar role in cell cycle progression/exit and differentiation of neuronal precursors during neurogenesis [24]
The studies described have revealed that Cend1 is a protein expressed all along the neuronal lineage, from neural stem/progenitor cells to mature neurons
Summary
Neural stem and progenitor cells are the building blocks of the brain In the embryo, these cells are located in proliferative zones and produce a variety of neurons and glia through tightly regulated processes that result in the generation of the diversity and complexity of the cellular phenotypes found in the adult brain [1,2,3,4,5,6,7,8]. NPCs proliferate in the ventricular and subventricular zones of the developing forebrain, exit the cell cycle, and differentiate as they migrate away from these zones During this process, coordinated regulation of cell cycle exit and differentiation is essential for generation of the appropriate number of neurons and formation of the correct structural and functional connections of neuronal circuits. We describe a recent finding that highlights its implication in Zika virus infection [25]
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