Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity

Abstract

Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.

Divide or Commit – Revisiting the Role of Cell Cycle Regulators in Adult Hippocampal Neurogenesis

“…Loss of CDK6 specifically prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration and premature CC exit, resulting in decreased neurogenesis (Beukelaers et al, 2011). The group of Caron et al (2018) then asked for the mechanism of CDK action in adult SGZ precursors. By generating mice bearing a kinase-dead allele of CDK6 they demonstrated that the function of CDK6 in hippocampal neurogenesis relies essentially on its kinase activity.…”

Silencing of lncRNA PKIA-AS1 Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain Through Epigenetic Downregulation of CDK6 Expression

“…The demonstrated involvement of CDKs in proinflammatory gene expression makes these proteins promising target for treatment of chronic inflammatory diseases. CDK6 has been implicated in the proliferation, differentiation, and survival of neurons (Beukelaers et al, 2011; Mi et al, 2013; Caron et al, 2018; Hasenpusch-Theil et al, 2018). For example, preventing CDK6 over-activation can reduce 6-hydroxy-dopamine-induced neuronal death (Alquezar et al, 2015).…”

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

“…During hippocampal neurogenesis, the proliferation of progenitor cells specifically relies on the p27-dependent regulation of MCPH12 kinase activity. CDK2, CDK4, and cyclin D1 were downregulated, whereas p21 (Waf1/Cip1) and p27 (Kip1) were upregulated in MCPH19 knockdown cells compared with in control cells [68]. The role of p27 in carcinogenesis was revealed through studies involving MCPH19 [82].…”

“…Regulating radial glial cells G1 and S phases [66] DNA damage response, apoptosis (epithelial ovarian cancer) [67] Positively regulates the proliferation of hippocampal progenitors [68] Cell cycle (glioblastoma) [69] Proliferation of neural stem cells [70] Cell cycle, cell proliferation and angiogenesis (hematopoietic malignancies) [71] Cell cycle and apoptosis (T-cell acute lymphoblastic leukemia) [72] MCPH13 (CENPE) N/A Cell G2/M phase and proliferation (lung cancer) [25] MCPH14 (SAS6) N/A Centrosome amplification, mitotic abnormality (CRCs) [73] MCPH15 (MFSD2A) Blood-brain barrier disruption [74] Cell cycle (G1 phase) and matrix attachment (lung cancer) [41] MCPH16 (ANKLE2) Reduced cell proliferation [75] N/A…”

“…As MCPH12 is a key gene in cell cycle regulation, it can also regulate neuronal output and cortical size [66]. In addition, during the development of the hippocampus, p27 can negatively regulate the expression of MCPH12, thereby regulating the proliferation of hippocampal cells [68]. During the development of the neocortex, the loss of MCPH17 mainly affects neurogenic divisions [76].…”