Antagonistic effects of Grg6 and Groucho/TLE on the transcription repression activity of brain factor 1/FoxG1 and cortical neuron differentiation.

Groucho (Gro)/TLE transcriptional corepressors are involved in a variety of developmental mechanisms, including neuronal differentiation. They contain a conserved C-terminal WD40 repeat domain that mediates interactions with several DNA-binding proteins. In particular, Gro/TLE1 interacts with forkhead transcription factor brain factor 1 (BF-1; also termed FoxG1). BF-1 is an essential regulator of neuronal differentiation during cerebral cortex development and represses transcription together with Gro/TLE1. Gro/TLE-related gene product 6 (Grg6) shares with Gro/TLEs a conserved WD40 repeat domain but is more distantly related at its N-terminal half. We demonstrate that Grg6 is expressed in cortical neural progenitor cells and interacts with BF-1. In contrast to Gro/TLE1, however, Grg6 does not promote, but rather suppresses, BF-1-mediated transcriptional repression. Consistent with these observations, Grg6 interferes with the binding of Gro/TLE1 to BF-1 and does not repress transcription when targeted to DNA. Moreover, coexpression of Grg6 and BF-1 in cortical progenitor cells leads to a decrease in the number of proliferating cells and increased neuronal differentiation. Conversely, Grg6 knockdown by RNA interference causes decreased neurogenesis. These results identify a new role for Grg6 in cortical neuron development and establish a functional link between Grg6 and BF-1.

Hes6 inhibits astrocyte differentiation and promotes neurogenesis through different mechanisms.

The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphology and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. They suggest further that separate molecular mechanisms underlie the proneuronal and anti-gliogenic activities of Hes6 in cortical progenitor cells.

Inhibition of cortical astrocyte differentiation by Hes6 requires amino- and carboxy-terminal motifs important for dimerization and phosphorylation.

Hairy/Enhancer of split (Hes) 6 is a basic helix-loop-helix protein that interacts with the transcriptional co-repressor, Groucho, and antagonizes the neural functions of the Notch pathway. More specifically, mouse Hes6 regulates cerebral corticogenesis by promoting neurogenesis and suppressing astrocyte differentiation. The molecular mechanisms underlying the anti-astrogenic function of Hes6 are poorly defined. Here we describe studies aimed at testing whether Hes6 inhibits astrocyte differentiation by antagonizing the transcription repression activity of Notch-activated Hes family members like Hes1. It is reported that Hes6 preferentially forms homodimers. Heterodimerization with Hes1 is antagonized in part by a conserved N-terminal patch of negatively charged residues. Mutation of this motif enhances heterodimerization with Hes1 and increases Hes6 ability to antagonize Hes1-mediated transcriptional repression. However, this mutation does not increase, but instead decreases, the anti-astrogenic activity of Hes6. It is shown further that Hes6 harbors a second conserved sequence, a C-terminal SPXXSP motif. This sequence is phosphorylated by the mitogen activated protein kinase pathway and its mutation disrupts the anti-astrogenic activity of Hes6 without affecting its ability to suppress Hes1. Together, these observations suggest that Hes6 homodimers regulate astrocyte differentiation through mechanisms that depend on the phosphorylation of Hes6 C-terminal domain but are independent of its ability to suppress Hes1-mediated transcriptional repression.

Function and comorbidities of apolipoprotein e in Alzheimer's disease.

Alzheimer's disease (AD)-the most common type of dementia among the elderly-represents one of the most challenging and urgent medical mysteries affecting our aging population. Although dominant inherited mutation in genes involved in the amyloid metabolism can elicit familial AD, the overwhelming majority of AD cases, dubbed sporadic AD, do not display this Mendelian inheritance pattern. Apolipoprotein E (APOE), the main lipid carrier protein in the central nervous system, is the only gene that has been robustly and consistently associated with AD risk. The purpose of the current paper is thus to highlight the pleiotropic roles and the structure-function relationship of APOE to stimulate both the functional characterization and the identification of novel lipid homeostasis-related molecular targets involved in AD.