Emerging roles for the BAI1 protein family in the regulation of … – NCBI

BAI family gene regulation and expression in development

Little is known regarding the mechanisms of transcriptional regulation and expression of the BAI1 gene family. BAI1 was initially identified in a screen for genes regulated by the tumor suppressor p53 [5] as a result of a putative p53 binding site located in its ninth intron on chromosome 8q24 (Fig. 2a), and was suggested to be a candidate paracrine effector for the anti-angiogenic effects of p53 [6]. Some studies have found that restoration of p53 expression in p53 mutant glioma cells can upregulate BAI1 mRNA [7], while others have not [8], suggesting this needs further study. The BAI1 promoter has predicted binding sites for a wide variety of transcription factors but their involvement has not been confirmed experimentally. Recently, studies of the mouse BAI1 gene have identified a second promoter located downstream of the GPS site, generating a variant of BAI1 lacking its extracellular domain and expressed in the hippocampus [9]. Further work is warranted to establish the expression pattern of these two independent promoters and their importance in different tissues.

The BAI 2 and 3 genes were discovered as a result of their homology with BAI1, and are localized at chromosomes 1p35 and 6q12, respectively. In contrast to BAI1, BAI2, and BAI3 are not known to contain p53-binding sites and p53 has not been demonstrated to regulate mRNA levels of either [7]. The promoters regulating the expression of these two genes have not been studied to date.

All BAI family transcripts are expressed in fetal and adult human brain tissue [7]. Expression of BAI1 mRNA is highly enriched in the brain compared with other tissues and specifically localized in neurons [10], glia, and macrophages [11]. The expression of BAI2 and BAI3 mRNA is more widely distributed; in addition to brain expression, both BAI2 and BAI3 mRNA are expressed in adult human heart tissue, and BAI2 mRNA is also detected in skeletal muscle and thymus, while BAI3 mRNA is found in testis and small intestine tissue specimens. Little is known about the expression of the BAI proteins themselves, however, and further research is necessary to determine their localization at the cellular level and gain insight into these proteins’ function in normal brain or elsewhere.

Studies of expression of BAI family members in mouse brain development have generally mirrored the findings in human tissue. Murine Bai1 mRNA expression, like that of human BAI1, is primarily brain specific and increases after birth to reach the highest level of expression at approximately P10. mBai1, which shares a 94% sequence identity with hBAI1, is expressed at high levels in cortical neurons, the pyramidal neurons of the hippocampus, the granular cell layer of the olfactory bulb, cerebellar Purkinje neurons, and in the craniofacial nerve nuclei [12]. As for hBAI1, further work is necessary to determine localization of the mBAI1 protein and what role it plays in these cell types.

In contrast, mBai2 and mBai3 mRNAs are expressed ubiquitously during embryonic development but largely restricted to the brain after birth. In the brain, the localization pattern of mBai2 is highly similar to that of mBai1. Notably, anti-mBai2 mRNA probes detected seven mRNA splice variants, some lacking such important functional features as the third cytoplasmic loop of the seven-transmembrane domain [13]. More recent work has determined that mBai3 continues to be expressed in the muscle-myenteric nerve layer of the adult mouse gastrointestinal tract [14]. Given their wide-ranging distribution, these proteins may serve biological functions in a wide range of tissue types.