The Drosophila Activin-like ligands Activin-β and Dawdle control several aspects of neuronal morphogenesis, including mushroom body remodeling, dorsal neuron morphogenesis and motoneuron axon guidance. Here we show that the same two ligands act redundantly through the Activin receptor Babo and its transcriptional mediator Smad2 (Smox), to regulate neuroblast numbers and proliferation rates in the developing larval brain. Blocking this pathway results in the development of larvae with small brains and aberrant photoreceptor axon targeting, and restoring babo function in neuroblasts rescued these mutant phenotypes. These results suggest that the Activin signaling pathway is required for producing the proper number of neurons to enable normal connection of incoming photoreceptor axons to their targets. Furthermore, as the Activin pathway plays a key role in regulating propagation of mouse and human embryonic stem cells, our observation that it also regulates neuroblast numbers and proliferation in Drosophilasuggests that involvement of Activins in controlling stem cell propagation may be a common regulatory feature of this family of TGF-β-type ligands.

How TGF-β-type ligands achieve signaling specificity during development is only partially understood. Here we show that Dawdle, one of four Activin-type ligands in Drosophila, preferentially signals through Baboc, one of three isoforms of the Activin Type-I receptor that are expressed during development. In cell culture, Dawdle signaling is active in the presence of the Type-II receptor Punt but not Wit, demonstrating that the Type-II receptor also contributes to the specificity of the signaling complex. During development, different larval tissues express unique combinations of these receptors, and ectopic expression of Baboc in a tissue were it is not normally expressed at high levels can make that tissue sensitive to Dawdle signaling. These results reveal a mechanism by which distinct cell types can discriminate between different Activin-type signals during development as a result of differential expression of Type-I receptor isoforms.

The telomeric P elements TP5 and TP6 are associated with the P cytotype, a maternally inherited condition that represses P-element-induced hybrid dysgenesis in the Drosophila germ line. To see if cytotype repression by TP5 and TP6 might be mediated by the polypeptides they could encode, hobo transgenes carrying these elements were tested for expression of mRNA in the female germ line and for repression of hybrid dysgenesis. The TP5 and TP6 transgenes expressed more germ-line mRNA than the native telomeric P elements, but they were decidedly inferior to the native elements in their ability to repress hybrid dysgenesis. These paradoxical results are inconsistent with the repressor polypeptide model of cytotype. An alternative model based on the destruction of P transposase mRNA by Piwi-interacting (pi) RNAs was supported by finding reduced P mRNA levels in flies that carried the native telomeric P elements, which are inserted in a known major piRNA locus.T RANSPOSABLE elements are significant components of the genomes of many organisms. These elements can cause gene mutations and chromosome breakage, and over evolutionary time, they can alter the composition and structure of genomes. There is, therefore, considerable interest in elucidating the mechanisms that foster or repress their activity. For example, many researchers have studied the regulation of P transposable elements in Drosophila melanogaster-a model family of elements in a model genetic organism (Engels 1989;Rio 1990).P elements are cut-and-paste transposons whose activity is catalyzed by an 87-kDa polypeptide, the P transposase, which is encoded by complete members of the P-element family (Karess and Rubin 1984;Rio et al. 1986). This polypeptide is restricted to the germ line because the last of the element's three introns is removed from P RNA only in that tissue . In somatic cells, retention of this intron results in the production of a 66-kDa polypeptide instead of the transposase. Tissue-specific splicing is therefore an important mechanism for controlling P-element activity. However even within the germ line, where the P transposase is made, P-element activity is regulated.Genetic evidence for this regulation was obtained from early studies that defined a maternally transmitted state called cytotype (Engels 1979;Kidwell 1981). The M cytotype permits P-element activity whereas the P cytotype represses it. Thus, when P elements are combined with the M cytotype by crossing P-bearing males to M-cytotype females, the P elements are mobilized in the offspring, where they cause a syndrome of germ-line abnormalities called hybrid dysgenesis (Kidwell et al. 1977;Engels 1989). This syndrome includes gonadal dysgenesis (GD) in both of the sexes, chromosome breakage, and elevated mutation rates. By contrast, crosses between P-bearing males and P-cytotype females produce offspring that seldom show dysgenic traits. These early studies also demonstrated that the P cytotype depends on the presence of P elements themselves (Engels 1979;Sved 1987); thus, t...

Animals use TGF-β superfamily signal transduction pathways during development and tissue maintenance. The superfamily has traditionally been divided into TGF-β/Activin and BMP branches based on relationships between ligands, receptors, and R-Smads. Several previous reports have shown that, in cell culture systems, “BMP-specific” Smads can be phosphorylated in response to TGF-β/Activin pathway activation. Using Drosophila cell culture as well as in vivo assays, we find that Baboon, the Drosophila TGF-β/Activin-specific Type I receptor, can phosphorylate Mad, the BMP-specific R-Smad, in addition to its normal substrate, dSmad2. The Baboon-Mad activation appears direct because it occurs in the absence of canonical BMP Type I receptors. Wing phenotypes generated by Baboon gain-of-function require Mad, and are partially suppressed by over-expression of dSmad2. In the larval wing disc, activated Baboon cell-autonomously causes C-terminal Mad phosphorylation, but only when endogenous dSmad2 protein is depleted. The Baboon-Mad relationship is thus controlled by dSmad2 levels. Elevated P-Mad is seen in several tissues of dSmad2 protein-null mutant larvae, and these levels are normalized in dSmad2; baboon double mutants, indicating that the cross-talk reaction and Smad competition occur with endogenous levels of signaling components in vivo. In addition, we find that high levels of Activin signaling cause substantial turnover in dSmad2 protein, providing a potential cross-pathway signal-switching mechanism. We propose that the dual activity of TGF-β/Activin receptors is an ancient feature, and we discuss several ways this activity can modulate TGF-β signaling output.