A Genetic Screen in Drosophila for Genes Interacting with Senseless during Neuronal Development Identifies the Importin Moleskin
Pepple, Kathryn L., Anderson, Aimée E., Frankfort, Benjamin J., Mardon, Graeme, Genetics
Senseless (Sens) is a conserved transcription factor required for normal development of the Drosophila peripheral nervous system. In the Drosophila retina, sens is necessary and sufficient for differentiation of R8 photoreceptors and interommatidial bristles (IOBs). When Sens is expressed in undifferentiated cells posterior to the morphogenetic furrow, ectopic IOBs are formed. This phenotype was used to identify new members of the sens pathway in a dominant modifier screen. Seven suppressor and three enhancer complementation groups were isolated. Three groups from the screen are the known genes Delta, lilliputian, and moleskin/DIM-7 (msk), while the remaining seven groups represent novel genes with previously undefined functions in neural development. The nuclear import gene msk was identified as a potent suppressor of the ectopic interommatidial bristle phenotype. In addition, msk mutant adult eyes are extremely disrupted with defects in multiple cell types. Reminiscent of the sens mutant phenotype, msk eyes demonstrate reductions in the number of R8 photoreceptors due to an R8 to R2,5 fate switch, providing genetic evidence that Msk is a component of the sens pathway. Interestingly, in msk tissue, the loss of R8 fate occurs earlier than with sens and suggests a previously unidentified stage of R8 development between atonal and sens.
SENS is a zinc-finger transcription factor that is necessary and sufficient for the development of the founding cell type of the Drosophila retina, the R8 photoreceptor (FRANKFORT et al. 2001; FRANKFORT and MARDON 2002). It is also necessary for development of the entire Drosophila peripheral nervous system (PNS). In the absence of Sens, sensory organ precursor (SOP) cells are specified but do not develop, and the corresponding sensory organs fail to form (NOLO et al. 2000). In addition, ectopic expression of Sens in the thorax generates amassive overproduction of mechanosensory bristles or macrochaete. These data indicate that sens acts near the top of the developmental cascade that specifies sensory organ fate. Furthermore, Sens is a member of a family of zinc-finger transcription factors termed the Gfi/Pag-3/Sens (GPS) proteins ( JAFAR-NEJAD and BELLEN 2004). These conserved proteins are required for normal neural development in many organisms including humans, mice (BELL et al. 1995), chicken (FUCHS et al. 1997), zebrafish (DUFOURCQ et al. 2004), Caenorhabditis elegans (JIA et al. 1996), and the house fly (KASAI and SCOTT 2001). In mammals, the Sens homolog Gfi-1 is involved in neurodevelopment of the inner ear hair cells (WALLIS et al. 2003) and cerebellar Purkinje cells (TSUDA et al. 2005). Mice lacking Gfi-1 are deaf and exhibit ataxia typical of inner ear balance defects (WALLIS et al. 2003).
Gfi-1 and its paralog Gfi-1b are also involved in hematopoiesis (ZENG et al. 2004; DUAN and HORWITZ 2005) and immune system function (SCHMIDT et al. 1998b; KARSUNKY et al. 2002; ZHU et al. 2002; HOCK et al. 2003; YUCELET al. 2003; ZENG et al. 2004; RATHINAM et al. 2005) and have been implicated in disease processes including neutropenia (KARSUNKY et al. 2002; PERSON et al. 2003), carcinogenesis (GILKS et al. 1993; SCHMIDT et al. 1996, 1998a; HOCK et al. 2004; KAZANJIAN et al. 2004; SHIN et al. 2004; DWIVEDI et al. 2005), and neurodegenerative disease (MOROY 2005; TSUDA et al. 2005). The expression of both sens and Gfi-1 is positively regulated by the bHLH proneural gene atonal/Math-5. In the absence of atonal in Drosophila, no adult eye is formed due to the failure of R8 photoreceptor specifi- cation (JARMAN et al. 1994). In mice, loss of Math-5 results in a severe reduction of Gfi-1 expression in the retina and loss of most retinal ganglion cells (BROWN et al. 2001; WANG et al. 2001; YANG et al. 2003). The remarkable similarity in function and regulation within the GPS family of proteins suggests that they are part of an evolutionarily conserved neurodevelopment pathway. …