T ‐Box Genes: Developmental Functions in Mammals

Abstract

Transcription factors encoded by the T‐box gene family control key functions throughout development in all metazoans. The DNA (deoxyribonucleic acid)‐binding domain is highly conserved. There are 17 genes in mouse and human, all with diverse functional roles from early embryogenesis through organogenesis and tissue homeostasis. The same gene may function in different tissues and at different stages such that mutation phenotypes can be complex. Most T‐box mutations display heterozygous defects, indicating dose sensitivity. Several T‐box genes affect pluripotency and differentiation in the pre‐ and early postimplantation embryo; limb outgrowth and differentiation is a major developmental area affected by T‐box genes as is the heart, nervous system, immune system and many other organs and tissues. T‐box gene loss‐of‐function mutations in humans cause major developmental syndromes such as ulnar‐mammary and Holt–Oram syndrome, and other abnormalities are increasingly being attributed to alteration in T‐box gene function, including the association with many types of cancer. Key Concepts T‐box genes code for transcription factors with diverse roles in development through regulation of a variety of downstream target genes. They comprise an ancient gene family present in all metazoans as well as nonmetazoan lineages, defined by a conserved DNA‐binding motif. In vertebrates, T‐box genes play diverse and key roles in specification, differentiation and development of most organ systems. Mutations in T‐box genes result in complex birth defects and/or neonatal lethality and usually show effects in heterozygotes and homozygotes. Multiple tissues may be affected by the same T‐box gene, and multiple T‐box genes may affect the same tissue at the same or different times in development. Mutation or misregulation of T‐box genes is associated with a large variety of human cancers. Little information is available about the role of T‐box genes in adult organisms.