Role of Krüppel-Like Factor 4 in Neurogenesis and Radial Neuronal Migration in the Developing Cerebral Cortex

Abstract

Transcription factors play key roles in the formation of a multilayered cerebral cortex consisting of neurons and glial cells. Krüppel-like factor 4 (KLF4) is expressed in neural stem cells and controls axonal regeneration. Its dysregulation leads to hydrocephalus in postnatal mouse brains. Here, we further show that KLF4 regulates neurogenesis and radial migration of neurons in the developing cerebral cortex. Neural progenitors with constitutive expression of KLF4 fail to migrate and develop into mature neurons but, rather, form cells with a glial identity. Notably, the JAK-STAT pathway is altered by KLF4, with increased phosphorylation of STAT3 at tyrosine 705. Blocking STAT3 activation with a dominant negative form can rescue the migration defect induced by constitutive KLF4 expression. Furthermore, downregulation of endogenous KLF4 significantly promotes radial migration and the transition of newly born migrating neurons from multipolar to bipolar morphology. Together, these results suggest that precise regulation of KLF4 expression is critical to neuronal differentiation and migration during the formation of a cerebral cortex.

Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway

“…We selected 5 predicted miR-7 target genes, each associated with the p53 pathway, and with known functions regulating differentiation or survival in neural development: a cytosolic adenylate kinase Ak1 , apoptotic activator Pmaip1 (also known as Noxa ), CDK inhibitor Cdkn1a (also known as p21 ), transcription factor Klf4 , and the cyclin Ccng1 (Akhtar et al, 2006; Lookeren Campagne and Gill, 1998; Noma et al, 1999; Qin and Zhang, 2012). Furthermore, all of them showed significant upregulation of expression levels in vivo due to loss of miR-7 function (Figure S6).…”

“…The p53 pathway, overlapping with those of its cortically expressed family members p63 and p73, is intimately linked to cell cycle checkpoint control and cell survival (Murray-Zmijewski et al, 2008). Verified miR-7 targets Ak1 and Klf4 have been implicated in neuronal differentiation (Inouye et al, 1998; Noma et al, 1999; Qin and Zhang, 2012). Ccng1 and p21 have been shown to promote cell cycle arrest that can lead to apoptosis (El-Deiry et al, 1993; Wade Harper et al, 1993).…”

APC/C-Cdh1 coordinates neurogenesis and cortical size during development

“…Alternatively, the accumulated pool of neural precursor cells in the VZ/SVZ of Cdh1 À / À cerebral cortex could be suggestive of a migration defect. Recently, Qin and Zhang 50 have described that downregulation of the APC/C-Cdh1 target KLF4 (ref. 51) is essential for normal neurogenesis.…”

“…51) is essential for normal neurogenesis. Similarly, neural progenitor cells with high expression of KLF4 fail to migrate and develop into neurons 50 . Future studies would be needed to fully understand the role of Cdh1 on neuronal migration during brain development.…”

The role of octamer binding transcription factors in glioblastoma multiforme

“…Among these TFs controlling the pluripotency of both NSCs and GSCs are OCT family TFs, SOX2, and the homeobox protein NANOG [5, 30, 31]. In addition to these TFs, other genes such as KLF4, REX1, Olig2, SALL2 and c-Myc are also pivotal in regulating the complex pluripotency circuitry in NSCs [32–36] and GSCs [4, 22, 23]. …”