Monica J. Justice

The progress of human genome sequencing is driving genetic approaches to define gene function. Strategies such as gene traps and chemical mutagenesis will soon generate a large mutant mouse resource. Point mutations induced by N -ethyl- N -nitrosourea (ENU) provide a unique mutant resource because they: (i) reflect the consequences of single gene change independent of position effects; (ii) provide a fine-structure dissection of protein function; (iii) display a range of mutant effects from complete or partial loss of function to exaggerated function; and (iv) discover gene functions in an unbiased manner. Phenotype-driven ENU screens in the mouse are emphasizing relevance to human clinical disease by targeting cardiology, physiology, neurology, immunity, hematopoiesis and mammalian development. Such approaches are extremely powerful in understanding complex human diseases and traits: the base-pair changes may accurately model base changes found in human diseases, and subtle mutant alleles in a standard genetic background provide the ability to analyze the consequences of compound genotypes. Ongoing mouse ENU mutagenesis experiments are generating a treasure trove of new mutations to allow an in-depth study of a single gene, a chromosomal region or a biological system.

Two families of homeo box-containing genes have been identified in mammals to date, the Antennapedia- and engrailed-like homeo boxes, based on the sequence similarity to those from Drosophila. Here, we report the isolation of a homeo box-containing gene that belongs to a new family of which there are at least three related genes in the mouse genome. The homeo box of this new gene shows remarkable similarity to the Drosophila Msh homeo box that we designate as the prototype for this family. The gene maps to the proximal end of mouse chromosome 5 and does not cosegregate with any known homeo box-containing gene. We designate this locus Hox-7.1. In situ hybridizations to mouse embryos at different stages show a unique pattern of expression, as compared to other homeo box-containing genes described thus far. Hox-7.1 transcripts are detected in 9.5-day-old embryos in the neural crest, developing limb bud, and visceral arches. Later, this gene is expressed in regions of the face that are derived from neural crest and in the interdigital mesenchymal tissues in both the fore- and hindlimbs.