Identification and functional analysis of a novel BTB-domain gene family.

Sobieszczuk, Dorota Felicja (2006). Identification and functional analysis of a novel BTB-domain gene family. PhD thesis The Open University.



In a screen for novel genes involved in chick hindbrain development, clone cVll was isolated, encoding a gene expressed in the hindbrain. Sequence analysis established that cVll is a novel gene, now designated cBTBD6, which encodes protein containing three functional domains: BTB, BACK and PHR. Human, mouse and zebrafish cBTBD6 orthologs were cloned, as well as highly related BTBD3 genes that form a distinct subgroup of the same family of genes. Within each subgroup there is a single copy of human, chick and mouse BTBD6 and BTBD3 and two copies of zebrafish orthologs. Spatio- temporal analysis of BTBD6 and BTBD3 expression patterns in chick and zebrafish revealed that, while BTBD3 othologs have divergent expressions, cBTBD6 shares some aspects of its expression pattern with its counterparts in zebrafish, zBTBD6a and zBTBD6b. In particular, both cBTBD6 and zBTBD6a are expressed in the developing central nervous system, suggesting a potential involvement in neurogenesis. This potential function was investigated in zebrafish. Comparative analysis of zBTBD6a expression with markers of neurogenesis revealed that zBTBD6a is expressed in cells during neuronal differentiation, starting from early stages labelled by proneural gene neurogl until later phases marked by isll, when zBTBD6a expression starts to be downregulated. Knockdown experiments demonstrated that zBTBD6a promotes neurogenesis and acts downstream of neurogl and upstream of neurod and neurod4 in the neurogenesis cascade. I found that zBTBD6a interacts with Cul-3, a component of the ubiquitin ligase complex, and the PHR motif and to a lesser extent the BTB domain are required for this interaction. Overexpression experiments showed that the presence of both BIB and PHR is required for zBTBD6a function. Since several BTB- containing proteins have been recently reported to be implicated in targeting proteins for ubiqutination, it is proposed that zBTBD6a positively regulates neurogenesis by mediating ubiquitination of one or more proteins that regulate the formation of neurons.

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