Cend1, a Story with Many Tales: From Regulation of Cell Cycle Progression/Exit of Neural Stem Cells to Brain Structure and Function

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.

LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway

“…Similarly, a critical role of APC2 in suppressing EOC progression has been demonstrated [76], as APC2 silencing promoted EOC cell proliferation [77] and was associated with decreased overall survival in EOC patients following intraperitoneal chemotherapy [78]. CEND1 (cell cycle exit and neuronal differentiation protein 1) plays an important role in neuronal differentiation by modulating cell cycle progression/exit or apoptosis of neuronal progenitors [79]. CEND1 was shown to suppress cell proliferation via modulating the cyclin D1 pathway, which is linked to its potential tumor suppressor functions, associated with proliferation inhibition of neuroblastoma cells [80].…”

Minibrain-related kinase/dual-specificity tyrosine-regulated kinase 1B implication in stem/cancer stem cells biology

“…We have also shown that the negative effect of DYRK1B in Neuro2A proliferation is reversed when DYRK1B is co-expressed with its interacting partner, the scaffolding protein RanBPM that inhibits DYRK1B function by facilitating its proteasomal decay[ 35 ]. In addition, we have demonstrated that the tripartite functional interactions between DYRK1B, RanBPM and the neuronal protein Cend1 (for cell cycle exit and neuronal differentiation 1; also known as BM88) regulate the balance between cellular proliferation and differentiation in Neuro2A cells, suggesting that the three proteins may also play a similar role in cell cycle progression/exit and differentiation of neural stem cells/neural progenitor cells (NSCs/NPCs) during neurogenesis[ 35 , 79 ]. In agreement, we recently found that DYRK1B is expressed during central nervous system (CNS) development and marks all along the neuronal lineage (Kokkorakis et al , 2020 unpublished data).…”

“…We have recently demonstrated that DYRK1B is expressed in the adult mouse brain and in cultured primary cortical neurons and we have first studied DYRK1B function in mouse neuroblastoma Neuro2A cells, a suitable model for studies of neuronal development. We found that DYRK1B overexpression in Neuro2A cells promotes cell cycle exit and neuronal differentiation, by promoting Cyclin D1 cytoplasmic relocation and its proteasomal degradation by 26S proteasome[ 35 , 79 ]. It is worthy of note that transient overexpression of DYRK1B in Neuro2A cells also promotes neuronal differentiation, as indicated by the increase of the mean neurite length by 2-fold and by the expression of the neuronal marker, βIII-tubulin, when Neuro2A cells were subjected to differentiation using retinoic acid[ 35 ].…”

“…In addition, we have demonstrated that the tripartite functional interactions between DYRK1B, RanBPM and the neuronal protein Cend1 (termed for cell cycle exit and neuronal differentiation 1; also known as BM88) regulate the balance between cellular proliferation and differentiation in Neuro2A cells, suggesting that the three proteins may also play a similar role in cell cycle progression/exit and differentiation of NSCs/NPCs during neurogenesis[ 35 , 79 ] (Figure 2 ). This is in agreement with the fact that both RanBPM and DYRK1B are expressed in neuronal precursors in parallel with Cend1[ 35 , 79 ]. Recently, we have found that DYRK1B is expressed in embryonic chick and mouse brain and spinal cord, and is highly expressed by cycling NSCs, while DYRK1B expression marks all along the neuronal lineage, suggesting thus DYRK1B implication in proliferation and differentiation of NSCs (Kokkorakis et al , 2020 unpublished data).…”

Association of CSF Proteins With Tau and Amyloid β Levels in Asymptomatic 70-year-olds 

“…To our knowledge TMEM132D has not been studied in the context of AD but we previously observed altered levels in patients with frontotemporal dementia (32). Other membrane bound proteins that showed strong associations to tau were CEND1, myelin oligodendrocyte glycoprotein (MOG), PIK3IP1 and VASN, which have various functions relevant to cell-cycle regulation, cell-adhesion and T-cell activation (60)(61)(62)(63).…”