Regulation of organ development by the NKX-homeodomain factors: an NKX code

Mammalian development is a highly coordinated process that involves sequential and time-dependent gene regulation. Deregulation of this process can have functional or morphological consequences, possibly causing lethality or organ dysfunction. Homeotic genes are considered the master regulators of early developmental processes. Of the many homeodomain genes, the NK2 class represents a family of phylogenetically ancient proteins. NK2 homeobox family members are tissue-specific transcription factors distinguished by a common DNA binding structure unique among the homeodomain genes. Increasing evidence indicates that individual Nkx factors are critical regulators of whole organ development. In the sections below, we review the structure, regulation, and expression of the NK2 gene family beginning with their discovery in Drosophila and relating the known features of vertebrate counterparts to the Drosophilaproteins. In particular, we note that each of the vertebrate NK2 proteins are associated with particular genetic anomalies leading to a variety of described disease states. Further, based upon our examination we propose a new paradigm of development based upon the regulatory capacity of the NK2 homeodomain proteins termed the "Nkx Code"