Disease relevance of Id4

• We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers [1].

Psychiatry related information on Id4

• Id4 appears in the neural tube much later than other Id genes [2].

High impact information on Id4

• Here, we report that Id4 is required for normal brain size, and regulates lateral expansion of the proliferative zone in the developing cortex and hippocampus [3].
• These observations, together with evidence for the premature differentiation of early cortical stem cells, indicate that Id4 has a unique and complex function in regulating neural stem cell proliferation and differentiation [3].
• These data suggest that Id4 transcription control is highly complex, involving both negative and positive regulatory elements, including a novel inhibitory function exerted by Sp1 and Sp3 transcription factors [4].
• To identify cis- and trans-acting factors that regulate Id4 gene expression, we have analyzed the promoter regulatory sequences of the human Id4 gene in transient transfections and gel mobility shift assays [4].
• Comparison of the expression patterns of the four mouse dnHLH genes revealed that Id4 expression differs from the more restricted expression of Id2 as well as from the widespread expression of Id1 and Id3 [5].

Biological context of Id4

• Id4 expression, which is up-regulated during embryogenesis, is restricted to specific cells of the central and peripheral nervous system [6].
• Mutually exclusive expression of two dominant-negative helix-loop-helix (dnHLH) genes, Id4 and Id3, in the developing brain of the mouse suggests distinct regulatory roles of these dnHLH proteins during cellular proliferation and differentiation of the nervous system [6].
• Transcription of the Id4 gene results in three RNA molecules of 3.7, 2.0 and 1.7 kb which are presumably a result of differential splicing and/or alternatively used polyadenylation sites within the 3' untranslated region [5].
• During embryogenesis, Id4 expression is up-regulated between day 9.5 and 13.5 of gestation [5].
• Id4 expression induces apoptosis in astrocytic cultures and is down-regulated by activation of the cAMP-dependent signal transduction pathway [7].

Anatomical context of Id4

• Id1, 2, and 3 are expressed in multiple tissues, whereas Id4 expression can only be detected in neuronal tissues and in the ventral portion of the epithelium of the developing stomach [8].
• Id4 mRNA was detected in the regions such as the caudate putamen and the lateral amygdaloid nucleus [9].
• Late-born cortical neurons and astrocytes in the cortex, septum, hippocampus and caudate putamen of Id4(-/-) adult brains were decreased, however, likely due to the depletion of the NPC pool [10].
• Although the number of apoptotic cells was significantly increased, the neocortex of Id4(-/-) embryos was consistently thicker due to premature neuronal differentiation, which resulted in an increase in early-born neurons in the adult Id4(-/-) cortex [10].
• Furthermore, overexpression of Id4 in an astrocyte-derived cell line induced cells to round up and die by apoptosis [7].

Associations of Id4 with chemical compounds

• Forskolin and pentoxifylline, two other agents known to elevate intracellular cyclic AMP through different mechanisms, also potently decreased Id4 gene expression [7].
• In these same cultures, treatment with dibutyryl-cyclic AMP, a cyclic AMP analogue known to promote astrocyte differentiation, dramatically and selectively decreased Id4 gene expression [7].

Other interactions of Id4

• In addition, the characteristic expression of Id2 and Id4 in more mature neurons is reiterated both in the PNS and in the neurons of some of the sensory organs [11].
• Within the detection limits of in situ hybridization, Id4 and Id3 expression is mutually exclusive in neural precursor cells of the developing brain, suggesting distinct regulatory functions for these dnHLH proteins during neurogenesis [6].
• In this study, we have analyzed the expression of the dominant negative HLH genes, Id1 to Id4 and the class A gene REB, during Schwann cell development [12].
• In vitro analysis of neurosphere cultures revealed that proliferation of Id4-deficient NPCs was impaired and that BMP2-mediated astrocyte differentiation was accelerated in the absence of Id4 [10].
• In the absence of Id4, the ventricular zone of the neocortex, future hippocampus as well as lateral and medial ganglionic eminences exhibited a 20-30% reduction in mitotic neural precursor cells (NPCs) [10].

Analytical, diagnostic and therapeutic context of Id4

• Sequence analysis indicated that the Id4 gene consists of three exons [13].

References