BIOLOGICAL OVERVIEW

Drosophila Serum response factor (SERF) has been shown to be allelic to blistered the preferred name for the gene. blistered is required for vein/intervein formation in the fly wing. Similarly, a mutation first known as pruned was isolated in a screen of Drosophila enhancer trap strains. Seen to have an affect on tracheal development, pruned also proved to be identical to blistered. blistered by any name is truely a gene with a multiple personality. In this report the gene will be referred interchangably as Serf or blistered.

Serf is expressed in the peripheral tracheal system during the late stages of the development of trachea. Many of the SERF containing nuclei belong to those tracheal cells closest to and in direct contact with the target tissues tracheated by particular branches, while cells tightly associated with the transverse connectives or with the lateral trunk do not express Serf. In flies where the chromosomal region for Serf has been deleted, defects have been observed in terminal tracheal branching. It appears that cells normally neighboring Serf-expressing cells in wild type act abnormally in Serf mutants. They do not properly stop their migration at the appropriate developmental stage, but rather appear to follow the leading cell of the branch, and eventually cluster in close proximity to the target tissue. Perhaps wild type tip cells leading outgrowing branches receive specific information upon contacting the target tissue and communicate this information to the following cells in order to arrest their migration (Affolter, 1994).

The cellular events leading to terminal branching in wild type cells begins when the terminal cell extends a cytoplasmic process. A lumen, or cavity, is present in the terminal cell, but only up to the level of the nucleus: the lumen is an early secondary tracheal branch. The cytoplasmic projection, becomes very thin as it extends along the surface of the target. The terminal cells of pruned mutants do not have long cytoplasmic projections beyond the cell body. In some cases rudimentary projections can be seen, but they never support a lumen. Thus, the absence of terminal branches in pruned mutants is a consequence of the failure of terminal cells to extend long cytoplasmic projections to their targets. The involvement of Serum response factor in the generation of cytoplasmic branches was tested by ectopically expressing the Mammalian SRF MADS box transcription factor in Drosophila. Constitutively active SRF drives formation of extra cytoplasmic projections within a single lumen. The cytoplasmic processes that form in cells expressing Mammalian SRF do not grow toward their usual targets but instead grow out in random directions, invading territories normally supplied by other tracheal branches (Guillemin, 1996).

The involvement of Serf in tracheal development recalls the involvement of Breathless, an FGF receptor homolog, in the terminal stages of tracheal development. Induction of a dominant-negative breathless construct after the tracheal branches are completed, blocks the formation of tracheoles (extensions of cellular processes by the terminal tracheal cells) demonstrating that Breathless plays an essential role in this later process, as well as in the earlier process of trachea outgrowth (Reichman-Fried, 1995). Perhaps Serf is a target of Breathless signaling. Since Breathless signaling involves the Ras pathway, perhaps Serf is a target of the Ras pathway.

Serf is expressed in the future intervein issue of the wing imaginal disc, in a complementary pattern to the EGF-R accessory gene rhomboid, and also complementary to araucan and caupolican which code for two divergent homeodomain proteins involved in establishing the prepattern for rhomboid. The genes myospheroid and inflated, coding for integrin subunits are expressed in intervein cells, while expression of the gene veinlet is restricted to the future vein tissue of the wing disc (Montagne, 1996, Sturtevant, 1993 and Gomez-Skarmeta, 1996).

In wing differentiation blistered/Serf plays a dual role in wing development. Two fully active copies of blistered/Serf are required to ensure that the formation of wing veins is limited to vein territories. In addition SERF protein is essential for proper terminal differentiation of intervein cells. One target of SERF appears to be rhomboid. rhomboid's range of expression broadens presumptive vein areas in Serf mutants to include cells normally fated to become intervein domains. A second target is likely to be myospheroid, which genetically interacts with blistered/Serf. Myospheroid is required for the tight apposition of dorsal and ventral surfaces of the wing; mutations in myospheroid result in blistered adult wings (Fristrom, 1994).

How might the roles of SERF in trachea and wing development find a common ground? In wing morphogenesis, around 18 hours after puparium formation, pairs of intervein cells on opposite dorsal and ventral surfaces undergo a process of apposition and become connected by basal extensions to form an intervein band. Later cells separate and undergo reapposition. Reapposition begins at the center of intervein regions and proceeds laterally, until by 30 hours, only vein channels remain unapposed. By 21 hours, vein cells begin to differentiate, undergoing a process of decrease in apical diameter. Vein cells become coated basally by a laminin-containing extracellular matrix, and laminin is subsequently cleared from the intervein regions. The process of formation of basal extentions, critical to the process of apposition, might be likened to the process of formation of cytoplasmic projections in tracheal terminal branching, a process involving changes in cell shape, undoubtedly based on cytoskeletal changes in the cell (Fristrom, 1994).

GENE STRUCTURE

Bases in 5' UTR - 375

Bases in 3' UTR - 482

PROTEIN STRUCTURE

Amino Acids - 450

date revised: 20 June 98

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