ReviewIroquois genes: genomic organization and function in vertebrate neural development
Introduction
The iroquois (Iro/Irx) genes encode a family of homeoproteins found from nematodes to humans [1]. In addition to a highly conserved homeodomain of the TALE (three amino acid loop extension) superclass, the Iro proteins share a 13 amino acid domain called the Iro box [1]. As summarized recently [2], they participate in many developmental processes, ranging from the specification of territories to the development of pattern elements like insect sensory organs and wing veins. We discuss first our understanding of the genomic organization of the Iro/Irx genes and later their function in specifying and subdividing the vertebrate neural territories during development.
Section snippets
Genomic organization
Whereas in Caenorhabditis elegans there is only one Iro/Irx gene, in Drosophila there are three clustered in 130 kb of genomic DNA—araucan, caupolican and mirror 3., 4.— and in mouse and humans there exist six. These are grouped in two genomic clusters (2.2 and 1Mb) of three genes each 5., 6•., 7., 8••., 9., 10. (Fig. 1). Complete sets of six genes have not yet been identified in either Xenopus, chick or zebrafish. However, six-gene sets most likely exist in these vertebrates, as at least one
Early function: specification of the neuroectoderm
The first Iro genes were identified in Drosophila as prepattern factors that regulate proneural genes 2., 22., 27.. Shortly after, three Xenopus Iro genes (Xiro1, 2 and 3) were found to participate, during early neurulation, in the regulation of vertebrate proneural genes 11., 12., 22., 23•.. More recently, Xiro genes have been shown to be essential during gastrulation to specify the neural territory [23•]. In Xenopus, formation of the neural plate requires suppression of the function of Bmp-4,
Conclusions and future directions
Many important aspects of the organization and function of iro genes remain to be clarified. For instance, when in evolution did the duplication events that generated the Iro and Irx complexes and the posterior duplication of the ancestral Irx cluster occur? The number and organization of Iro genes in different phyla should be analyzed. It is also of interest to determine the extent of conservation of cis-regulatory elements between invertebrate and vertebrate and within vertebrate Iro/Irx
Update
Two recent publications cast some light on the effect of removing Iro/Irx gene function. The first one [43] shows that the mouse mutation Fused toes (Ft) is associated with a deletion that removes six genes including the whole IrxB cluster. Embryos homozygous for Ft die and show severe deformations of craniofacial and forebrain structures, disorganization of the ventral spinal chord, polydactyly and syndactyly, malformation of heart and random left–right asymmetry. As the Iro/Irx genes are
Acknowledgements
We are grateful to S Campuzano, JF de Celis, R Diez del Corral, M Ruiz-Gómez, K Storey and colleagues of our laboratory for constructive criticism of the manuscript, and to T Ogura for communication of unpublished data. JL Gómez-Skarmeta is a Ramón y Cajal Program investigator. Grants from Human Frontier Science Program (RG0042/98B), Dirección General de Investigación Cientı́fica y Técnica (PB98-0682, BMC2001-2122) and an institutional grant from Fundación Ramón Areces to the Centro de
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
• of special interest
•• of outstanding interest
References (46)
- et al.
araucan and caupolican, two members of the novel Iroquois complex, encode homeoproteins that control proneural and vein forming genes
Cell
(1996) - et al.
Identification of the vertebrate Iroquois homeobox gene family with overlapping expression during early development of the nervous system
Mech Dev
(1997) - et al.
Expression of two novel mouse iroquois homeobox genes during neurogenesis
Mech Dev
(2000) - et al.
Patterning the embryonic heart: identification of five mouse iroquois homeobox genes in the developing heart
Dev Biol
(2000) - et al.
Expression of a zebrafish iroquois homeobox gene, Ziro3, in the midline axial structures and central nervous system
Mech Dev
(1999) - et al.
Expression of two novel zebrafish iroquois homologues (ziro1 and ziro5) during early development of axial structures and central nervpus system
Mech Dev
(2001) - et al.
Sequence and expression pattern of ziro7, a novel, divergent zebrafish iroquois homeobox gene
Mech Dev
(2001) - et al.
c-Irx2 expression reveals an early subdivision of the neural plate in the chick embryo
Mech Dev
(1999) - et al.
Gene and cluster-specific expression of the Iroquois family members during mouse development
Mech Dev
(2001) - et al.
A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube
Cell
(2000)