An Essential Role for a MEK-C/EBP Pathway during Growth Factor-Regulated Cortical Neurogenesis

Abstract

Mammalian neurogenesis is determined by an interplay between intrinsic genetic mechanisms and extrinsic cues such as growth factors. Here we have defined a signaling cascade, a MEK-C/EBP pathway, that is essential for cortical progenitor cells to become postmitotic neurons. Inhibition of MEK or of the C/EBP family of transcription factors inhibits neurogenesis while expression of a C/EBPbeta mutant that is a phosphorylation-mimic at a MEK-Rsk site enhances neurogenesis. C/EBP mediates this positive effect by direct transcriptional activation of neuron-specific genes such as Talpha1 alpha-tubulin. Conversely, inhibition of C/EBP-dependent transcription enhances CNTF-mediated generation of astrocytes from the same progenitor cells. Thus, activation of a MEK-C/EBP pathway enhances neurogenesis and inhibits gliogenesis, thereby providing a mechanism whereby growth factors can selectively bias progenitors to become neurons during development.

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

“…6,7 In addition to its effects on general transcriptional potency, MEK-dependent phosphorylation of C/EBPb at Thr 188 biases cortical progenitors towards a neuronal fate in the developing CNS. 10,11 Although it is not yet known whether stress-induced MKP-1 antagonizes the pro-survival function of C/EBPb in the injured adult nervous system, we found that loss of C/EBPb expression in hypoxic neurons promotes cell death in vitro, 12 suggesting the stoichiometric relationship between the available pool of bZIP heterodimeric partners particularly important. 12,13 In the present study, we test the hypothesis that MKP-1 serves a molecular switch, exerting similar suppressive effects on the pro-survival factor C/EBPb following ischemic injury as has previously been described for HIF-1a.…”

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

“…During development, c/EBP-β signaling biases precursor cells to commit to a neural rather than glial lineage (Menard et al, 2002). c/EBP-β activity also induces axonal sprouting after axotomy, and, not surprising, regulates the expression of the neuronal markers NeuN, GAP43 and βIII tubulin (Nadeau et al, 2005).…”

CCAAT/Enhancer-binding Protein Family Members Recruit the Coactivator CREB-binding Protein and Trigger Its Phosphorylation

“…This domain consists of a basic region, contacting DNA, and a homo-or heterodimer-forming region called the leucine zipper (9). Because of the high conservation in the bZIP domain, C/EBP family members are able to form homo-or heterodimers, and all, except C/EBP , bind to the same cis-regulatory elements.C/EBP␣, C/EBP␤, and C/EBP␦ are involved in terminal differentiation of a variety of cells including adipocytes (10), hepatocytes (11,12), gut epithelial cells (13), macrophages (14), myelomonocytes (15), and neurons (16,17). In the nervous system, the role of C/EBP family members is not characterized as well as, for instance, in adipocytes or hepatocytes.…”

“…C/EBP␣, C/EBP␤, and C/EBP␦ are involved in terminal differentiation of a variety of cells including adipocytes (10), hepatocytes (11,12), gut epithelial cells (13), macrophages (14), myelomonocytes (15), and neurons (16,17). In the nervous system, the role of C/EBP family members is not characterized as well as, for instance, in adipocytes or hepatocytes.…”

“…In the nervous system, the role of C/EBP family members is not characterized as well as, for instance, in adipocytes or hepatocytes. However, a recent study suggests that they are essential for cortical progenitor cells to become postmitotic neurons (16). Interestingly, certain C/EBP isoforms appear to be involved in learning and memory processes (18 -20), glial or neuronal cell functions (21)(22)(23), and neurotrophic factor expression (24).…”