Disease relevance of Nfia

• Rare surviving homozygous Nfia(-/-) mice lack a corpus callosum, show severe communicating hydrocephalus, a full-axial tremor indicative of neurological defects, male-sterility, low female fertility, but near normal life spans [1].
• Finally, unlike their interaction with the NFI consensus binding site in the adenovirus promoter, the DNA-binding specificities of the three NFI isoforms to the palindromic NFI site in the WAP CoRE were not identical, which may partially explain the failure of the NFI-A isoform to cooperate with GR and STAT5A [2].
• Interaction of the TGGCA-binding protein with upstream sequences is required for efficient transcription of mouse mammary tumor virus [3].
• In the present report, we examine the disposition of PS NTF and CTF assemblies in stable mouse N2a neuroblastoma cell lines expressing human PS polypeptides [4].
• A single local s.c. injection of PLGA microspheres loaded with low amounts of PEX or PF-4/CTF resulted in an 88% and 95% reduction in glioma tumor volume 30 days post-treatment [5].

High impact information on Nfia

• A high-affinity binding site for the TGGCA-binding protein, also known as nuclear factor I, has previously been shown to reside within the mouse mammary tumor virus (MMTV) long terminal repeat [3].
• These findings indicate that while the Nfia gene appears nonessential for cell viability and DNA replication in embryonic stem cells and fibroblasts, loss of Nfia function causes severe developmental defects [1].
• We showed previously that Nfia-deficient mice exhibit agenesis of the corpus callosum and other forebrain defects, whereas Nfic-deficient mice have agenesis of molar tooth roots and severe incisor defects [6].
• In addition, loss of Nfib results in defects in basilar pons formation and hippocampus development that are not seen in Nfia-deficient mice [6].
• In contrast, the NFI-A isoform suppressed GR and STAT cooperativity at the WAP CoRE [2].

Biological context of Nfia

• The four genes exhibit unique but overlapping patterns of expression during embryonic development, with high level expression of NFI-A, NFI-B, and NFI-X transcripts in neocortex and extensive expression of the four genes in muscle, connective tissue, liver, and other organ systems [7].
• This prompted us to analyze the putative ability of CTF-PS2 to modulate cell death [8].
• They are encoded by four different genes (NFI-A, B, C, and X) each of which generates multiple isoforms by alternative RNA splicing [9].
• The Nuclear Factor I (NFI) family of site-specific DNA-binding proteins (also known as CTF or CAAT box transcription factor) functions both in viral DNA replication and in the regulation of gene expression [10].
• Three regulatory sequences in this region have been defined by deletion and mutagenesis: a consensus CTF/NF-1 site at -55, an Ets homology sequence at -65, and a degenerate, but crucial, SP-1 site at -100 [11].

Anatomical context of Nfia

• Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice [12].
• Of most interest is our observation that CTF-PS2 expression also triggers increased caspase 3 activity and immunoreactivity in fibroblasts in which presenilins had been deleted [8].
• CTF/NF-1-dependent promoter activity is also suppressed in 3T3-L1 cells during active growth (relative to the quiescent state) [13].
• The TGGCA-binding protein from HeLa cells appears to be identical to nuclear factor I described by others, which stimulates initiation of adenovirus DNA replication in vitro [14].
• RESULTS: PEX and PF-4/CTF released in vitro from PLGA microspheres were biologically active and significantly inhibited the proliferation of human umbilical vein endothelial cells, bovine capillary endothelial cells, and U87-MG cells [5].

Associations of Nfia with chemical compounds

• Furthermore, analyses of gene knockout mice revealed that Nfia is specifically required for normal expression of the GABRA6 gene in cerebellar granule neurons [15].
• PS1 and PS2 are polytopic membrane proteins that undergo endoproteolytic cleavage to generate stable NH2- and COOH-terminal derivatives (NTF and CTF, respectively) [4].
• We show that aspartate-mutant holoprotein presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes [16].

Regulatory relationships of Nfia

• NFI-A protein is expressed in all three midline populations [12].

Other interactions of Nfia

• The four NFI gene products studied differ in their ability to activate expression of the NFI-dependent MMTV promoter, with the NFI-B protein being most active and the NFI-A protein being least active [7].
• Disruption of the Nfia gene causes agenesis of the corpus callosum (ACC), hydrocephalus, and reduced GFAP expression (das Neves et al., 1999) [12].

Analytical, diagnostic and therapeutic context of Nfia

• Within this region of DNA, sequence analysis revealed a possible cAMP regulatory element, a CTF/NF-1 recognition sequence, two potential Sp1 sites, and five potential binding sites for transcription factor AP-2 [17].
• EXPERIMENTAL DESIGN: Polymeric microspheres made of poly(lactic-co-glycolic acid) (PLGA) were loaded with very low amounts of PEX and PF-4/CTF [5].

References