Mammalian Homologues of the Drosophila melanogaster flightless I Gene Involved in Early Development

H.   D.   Campbell; I.   G.   Young; K.   I.   Matthaei

Abstract

The many obvious differences between simple and more complex multicellular organisms mask the extraordinarily high degree of conservation of the basic life processes and the proteins involved in them. The evolutionary conservation of many essential genes allows knowledge gained from mutational studies in simpler organisms to be used to identify the corresponding genes in mammals. The function of mammalian homologues can then be investigated by gene targeting in mice. Early development in the fruitfly Drosophila melanogaster is far more accessible to investigation than corresponding mammalian processes and many interesting genes involved in early development in this organism have been identified and isolated. Embryos carrying null alleles of the Drosophila melanogaster flightless I (fliI) gene exhibit only partial cellularization and gastrulation fails. Weak alleles of fliI result in adult flies lacking flight ability and exhibiting abnormal indirect flight muscle ultrastructure. The fliI gene was pos itionally cloned and the predicted protein of 1256 amino acids found to contain leucine-rich-repeat (LRR) and gelsolin-like domains. Homologues of fliI have subsequently been cloned from C. elegans, human (FLII) and mouse (Fliih) via PCR. FLII maps to 17p11.2, into a region affected in Smith-Magenis syndrome and in childhood primitive neuroectodermal tumours. The gelsolin domain interacts with G-actin in a Ca2+-independent manner, and has F-actin binding and severing activities. FLAP1 and FLAP2, novel ligands for the LRR domain detected in the yeast two-hybrid system, are derived from related mammalian genes. FLAP2 has been independently reported as an HIV-1 TAR RNA binding protein and as a transcriptional repressor. The LRR has been shown to interact with Ras both in vitro, and in vivo in yeast. Genomics-based studies on fliI and its homologues have opened up their involvement in a novel pathway of cytoskeletal regulation which appears to play an essential role in early development.

Keywords: Drosophila melanogaster flightless I Gene, Fliih, Human FLlII, Mouse homologues, FLII, Flightless 1 mutations, Human FLII, PNETs, Primitive neuroectodermal tumors, LRR Domain