PACAP signaling to DREAM: A cAMP-Dependent Pathway that Regulates Cortical Astrogliogenesis

Abstract

Astrocytes constitute a very abundant cell type in the mammalian central nervous system and play critical roles in brain function. During development, astrocytes are generated from neural progenitor cells only after these cells have generated neurons. This so called gliogenic switch is tightly regulated by intrinsic factors that inhibit the generation of astrocytes during the neurogenic period. Once neural progenitors acquire gliogenic competence, they differentiate into astrocytes in response to specific extracellular signals. Some of these signals are delivered by neurotrophic cytokines via activation of the gp130-JAK-signal transducer and activator of transcription system, whereas others depend on the activity of pituitary adenylate cyclase-activating polypeptide (PACAP) on specific PAC1 receptors that stimulate the production of cAMP. This results in the activation of the small GTPases Rap1 and Ras, and in the cAMP-dependent entry of extracellular calcium into the cell. Calcium, in turn, stimulates the transcription factor downstream regulatory element antagonist modulator (DREAM), which is bound to specific sites of the promoter of the glial fibrillary acidic protein gene, stimulating its expression during astrocyte differentiation. Lack of DREAM in vivo results in alterations in the number of neurons and astrocytes generated during development. Thus, the PACAP-cAMP-Ca(2+)-DREAM signaling cascade constitutes an important pathway to activate glial-specific gene expression during astrocyte differentiation.

Critical Time Window of Neuronal Cholesterol Synthesis during Neurite Outgrowth

“…Because astrocytes are generated after neurogenesis has been practically completed (Vallejo, 2009), microglia likely provide cholesterol for newly committed mutant projection neurons in embryonic brain. Microglial lipoprotein particles containing ApoE ameliorate mevastatininduced neuronal death in vitro (Xu et al, 2000), and lipoprotein particles can be used as a cholesterol source for axon growth (Hayashi et al, 2004).…”

“…These neurons could be more sensitive to cholesterol deprivation because neuronal membrane expansion is high in the embryonic brain. In addition, potential support from astrocytes is limited as most astrocytes are born postnatally (Vallejo, 2009). We analyzed SQS/Nex-cre mice in which Cre under the control of the Nex (also referred to as Neurod6 ) promoter mediates the inactivation of SQS in virtually all newly committed, postmitotic cortical projection neurons as they are born between E11.5 and E16.5 (Goebbels et al, 2006;Molyneaux et al, 2007).…”

Developmental control of cortico-cerebral astrogenesis

“…A last trans-active pathway modulating cortico-cerebral astrogenesis is controlled by a ligand structurally related to Vasoactive Intestinal Peptide (Vip), termed Pituitary Adenylate CyclaseActivating Polypeptide (Pacap) (Vallejo, 2009). Cortical precursors express predominantly the short isoform of the Pacap-specific receptor Pac1, which couples to adenylate cyclase.…”

DREAM regulates insulin promoter activity through newly identified DRE element

“…Calsenilin is also required for endocrine pancreas development in zebrafish [19]. Secondly, there is abundance of data on the interactions of DREAM with DRE of genes coding certain hormones and hormone receptors as thyroid stimulating hormone receptor [20], glial fibrillary acidic protein gene [21,22], neuropeptide FF [23] calcitonin [24], and thyreoglobulin [6]. The repression of transcription by DREAM bound to DNA is regulated not only by changes in intracellular concentrations of Ca 2+ but also through an interaction with nuclear effector proteins of cAMP-induced signaling.…”