Lessons from lethal albino mice Introduction Gavin Kelsey and Giinther Schlitz German Cancer Research Center, Heidelberg, Germany Results from the analysis of mice homozygous for lethal albino deletions suggested the existence of a locus involved in the regulation of gene expression in the liver. The surprising finding that the locus encodes an enzyme active in tyrosine metabolism forces us to re-evaluate the lethal albino phenotype and advises caution in the interpretation of seemingly simple phenotypes. Current Opinion in Genetics and Development 1993, 3:259-264 As a model for elucidating the role of transcriptional reg- ulation in vertebrate development, the laboratory mouse offers two unique advantages. Firstly, the advent of homo- logous recombination in embryonic stem cells has al- lowed us to create mutations in regulatory genes at will, and to study the consequences of these targeted muta- tions in the differentiated cells of the resulting animal [ 11. Secondly, there exists a large number of ‘classical’ mutations, either experimentally induced or fortuitously discovered [ 21. The associated phenotypes suggest that many mutations affect the regulation of specific differen- tiation processes, and the molecular basis of some of the mutations has been elucidated [3]. lethal albino deletions in the mouse One genetic resource in the mouse is provided by clus- ters of overlapping chromosomal deletions recovered around visible ‘tester’ loci following radiation or chemi- cal mutagenesis [4]. The albino-deletion complex, a set of deletions that includes the albino (c) locus on chro- mosome 7, serves as a prototype for the convergence of genetic, embryological and molecular studies in the analysis of a discrete segment of the mouse genome [4,5]. Homozygotes for many of the deletions fail to survive beyond particular pre- or postnatal stages. Em- bryological and complementation analyses suggest that the albino-deletion complex defines six loci essential for normal development [5], and additional loci are being uncovered by chemical mutagenesis [6]. Some of these loci might encode regulatory functions, and the chromo- somal deletion studies will greatly assist in the identifica- tion of the respective genes [ 51, Deletions belonging to two of the albino complementa- tion groups allow development to birth, but the homo- zygotes die during the first postnatal day. (For the pur- pose of this review, the term lethal albino is restricted to the neonatal lethal phenotype and the corresponding albino deletions.) The homozygotes are severely hypogly- caemic, which possibly contributes to their death, owing to a failure to express high, neonatal levels of glucose- 6-phosphatase (GbPase) and other enzymes in the liver and kidney associated with gluconeogenesis [ 7~31. Since the structural genes for these enzymes do not map to the albino-deletion complex, and because activities of many other enzymes are normal, it was suggested that a regulatory locus required for the perinatal activation of a discrete set of genes in the liver had been deleted, as discussed in a recent review [ 9*]. The locus is defined as alf (from factor indicated by the lethal albino deletion; [ lo]) or hsdr- 2 (from hepatocyte-specific developmen- tal regulation 1; [ 11) >. This review focuses on develop- ments that initially complicated our understanding of the phenotype but which now, with the identification of the missing gene, can readily be interpreted. A simple hypothesis challenged by detailed phenotypic analysis Much effort has gone into listing genes whose expres- sion is altered in the lethal albino liver, such that, by seeking a common denominator in their normal reg- ulation, the molecular defect could be identified [lo]. Many of the affected genes were found to be under hormonal induction in the neonatal liver, notably by glucocorticoids and/or cyclic (c)-AMP, but this activa- tion appeared to fail in lethal albino mice [ 121. The absence of glucocorticoid but not heavy metal induc- Abbreviations AP-l-activating protein 1; CAMP-cyclic-AMP; C/EBP-CCAAT/enhancer-binding protein; CHOP-C/EBP-homologous protein; FAH-fumarylacetoacetate hydrolase; C6Pase-glucose-6-phosphatase; gadd-growth arrest and DNA damage; Hnf-hepatic nuclear factor; HT-hereditary tyrosinaemia type I; NF-xB-nuclear factor xB; Nmo-1-NAD(P)H:oxidoreductase; PEPCK-phosphoenolpyruvate carboxykinase; TAT-tyrosine aminotransferase. C @ Current Biology Ltd ISSN 0959-437X 259