What's new in edition 47 part 1/5 September 2006 Gene sites new with this edition

The Interactive Fly was first released July/August 1996, with updates provided at approximately one month intervals, through September 1997 (edition 13). Updating quarterly started with edition 14. With edition 40, the Interactive Fly began to schedule updates three times a year: fall, winter and spring.

The 'What's New' sections are more accurately termed, 'Some of What's New'. Every new gene site is included, but only about 10% of the information added to previously included gene sites is listed in the What's New sections for any given edition.

Gene sites new with this edition of the Interactive Fly:

Cad99C

Actin-based protrusions can form prominent structures on the apical surface of epithelial cells, such as microvilli. Several cytoplasmic factors have been identified that control the dynamics of actin filaments in microvilli. However, it remains unclear whether the plasma membrane participates actively in microvillus formation. The function of Drosophila melanogaster cadherin Cad99C in the microvilli of ovarian follicle cells has been analyzed. Cad99C contributes to eggshell formation and female fertility and is expressed in follicle cells, which produce the eggshells. Cad99C specifically localizes to apical microvilli. Loss of Cad99C function results in shortened and disorganized microvilli, whereas overexpression of Cad99C leads to a dramatic increase of microvillus length and results in large bundles of microvilli. Altered microvilli morphology correlates with defects in the assembly of the vitelline membrane, an extracellular layer secreted by follicle cells that is part of the eggshell. Cad99C that lacks most of the cytoplasmic domain, including potential PDZ domain-binding sites, still promotes excessive microvillus outgrowth, suggesting that the amount of the extracellular domain determines microvillus length. Cad99C is thus a critical regulator of microvillus length, the first example of a transmembrane protein that is involved in this process (D'Alterio, 2005; Schlichting, 2006).

Calnexin 99A

In sensory neurons, successful maturation of signaling molecules and regulation of Ca²⁺ are essential for cell function and survival. A multifunctional role for calnexin has been demonstrated as both a molecular chaperone uniquely required for rhodopsin maturation and a regulator of Ca²⁺, which enters photoreceptor cells during light stimulation. Mutations in Drosophila calnexin lead to severe defects in rhodopsin (Rh1) expression, whereas other photoreceptor cell proteins are expressed normally. Mutations in calnexin also impair the ability of photoreceptor cells to control cytosolic Ca²⁺ levels following activation of the light-sensitive TRP channels. Finally, mutations in calnexin lead to retinal degeneration; this degeneration is enhanced by light, suggesting that calnexin's function as a Ca²⁺ buffer is important for photoreceptor cell survival. These results illustrate a critical role for calnexin in Rh1 maturation and Ca²⁺ regulation and provide genetic evidence that defects in calnexin lead to retinal degeneration (Rosenbaum, 2006).

Chameau

Gene regulation by AP-1 transcription factors in response to Jun N-terminal kinase (JNK) signaling, controls essential cellular processes during development and in pathological situations. The histone acetyltransferase (HAT) Chameau and the histone deacetylase DRpd3 act as antagonistic cofactors of DJun and DFos to modulate JNK-dependent transcription during pupal thorax metamorphosis and JNK-induced apoptosis in Drosophila. It has been demonstrated, in cultured cells, that DFos phosphorylation mediated by JNK signaling plays a central role in coordinating the dynamics of Chameau and DRpd3 recruitment and function at AP-1-responsive promoters. Activating the pathway stimulates the HAT function of Chameau, promoting histone H4 acetylation and target gene transcription. Conversely, in response to JNK signaling inactivation, DRpd3 is recruited and suppresses histone acetylation and transcription. This study establishes a direct link among JNK signaling, DFos phosphorylation, chromatin modification, and AP-1-dependent transcription and its importance in a developing organism (Miotto, 2006).

Dystrophin

Mutations in the human dystrophin gene cause the Duchenne and Becker muscular dystrophies. The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin has also been found to act as a scaffold for several signaling molecules, but the roles of dystrophin-mediated signaling pathways remain unknown. To further an understanding of this aspect of the function of dystrophin, Drosophila mutants that lack the large dystrophin isoforms were generated and their role in synapse function at the neuromuscular junction was analyzed. In expression and rescue studies, lack of the large dystrophin isoforms in the postsynaptic muscle cell were shown to lead to elevated evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size, the size of the readily releasable vesicle pool as assessed with hypertonic shock, and the number of presynaptic neurotransmitter release sites (active zones) are not changed in the mutants. Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence of dystrophin results in increased probability of release. Absence of the large dystrophin isoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor function does not appear to be affected. These results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis (van der Plas, 2006).

Hand

The Hand gene family encodes highly conserved basic helix-loop-helix (bHLH) transcription factors that play crucial roles in cardiac and vascular development in vertebrates. In Drosophila, a single Hand gene is expressed in the three major cell types that comprise the circulatory system: cardioblasts, pericardial nephrocytes and lymph gland hematopoietic progenitors. Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation. Disruption of Hand function by homologous recombination also results in profound cardiac defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic cells, accompanied by cardiac apoptosis. Targeted expression of Hand in the heart completely rescues the lethality of Hand mutants, and cardiac expression of a human HAND gene, or the caspase inhibitor P35, partially rescues the cardiac and lymph gland phenotypes. These findings demonstrate evolutionarily conserved functions of HAND transcription factors in Drosophila and mammalian cardiogenesis, and reveal a previously unrecognized requirement of Hand genes in hematopoiesis (Han, 2006).

Iab-4/infraabdominal

The Drosophila Bithorax Complex encodes three well-characterized homeodomain proteins that direct segment identity, as well as several noncoding RNAs of unknown function. This study analyzes the iab-4 locus, which produces the microRNAs iab-4-5p and iab-4-3p. iab-4 is analogous to miR-196 in vertebrate Hox clusters. Previous studies demonstrated that miR-196 interacts with the Hoxb8 3' untranslated region. Evidence is presented that miR-iab-4-5p directly inhibits Ubx activity in vivo. Ectopic expression of mir-iab-4-5p attenuates endogenous Ubx protein accumulation and induces a classical homeotic mutant phenotype: the transformation of halteres into wings. These findings provide the first evidence for a noncoding homeotic gene and raise the possibility that other such genes occur within the Bithorax complex (Ronshaugen, 2005).

Inner centromere protein

The chromosomal passenger protein complex has emerged as a key player in mitosis, with important roles in chromatin modifications, kinetochore-microtubule interactions, chromosome bi-orientation and stability of the bipolar spindle, mitotic checkpoint function, assembly of the central spindle and cytokinesis. The inner centromere protein (Incenp; a subunit of this complex) is thought to regulate the Aurora B kinase and target it to its substrates. To explore the roles of the passenger complex in a developing multicellular organism, a genetic screen was performed looking for new alleles and interactors of Drosophila Incenp. A new null allele of Incenp has been isolated that has allowed a study of the functions of the chromosomal passengers during development. Homozygous incenp^EC3747 embryos show absence of phosphorylation of histone H3 in mitosis, failure of cytokinesis and polyploidy, and defects in peripheral nervous system development. These defects are consistent with depletion of Aurora B kinase activity. In addition, the segregation of the cell-fate determinant Prospero in asymmetric neuroblast division is abnormal, suggesting a role for the chromosomal passenger complex in the regulation of this process (Chang, 2006).

Lesswright/Ubc9

The lesswright (lwr) or semushi gene encodes an enzyme, Ubc9, that conjugates a small ubiquitin-related modifier (SUMO). Since the conjugation of SUMO occurs in many different proteins, a variety of cellular processes probably require lwr function. This study demonstrates that lwr function regulates the production of blood cells (hemocytes) in Drosophila larvae. lwr mutant larvae develop many melanotic tumors in the hemolymph at the third instar stage. The formation of melanotic tumors is due to a large number of circulating hemocytes, which is approximately 10 times higher than those of wild type. This overproduction of hemocytes is attributed to the loss of lwr function primarily in hemocytes and the lymph glands, a hematopoietic organ in Drosophila larvae. High incidences of Dorsal (Dl) protein in the nucleus were observed in lwr mutant hemocytes, and the dl and Dorsal-related immunity factor (Dif) mutations were found to be suppressors of the lwr mutation. Therefore, the lwr mutation leads to the activation of these Rel-related proteins, key transcription factors in hematopoiesis. Also demonstrate was the fact that dl and Dif play different roles in hematopoiesis. dl primarily stimulates plasmatocyte production, but Dif controls both plasmatocyte and lamellocyte production (Huang, 2005). Similar results have been reported by Chiu (2005). Loss-of-function mutations in dUbc9 cause strong mitotic defects in larval hematopoietic tissues, an increase in the number of hematopoietic precursors in the lymph gland and of mature blood cells in circulation, and an increase in the proportion of cyclin-B-positive cells. In the larval fat body, dUbc9 negatively regulates the expression of the antifungal peptide gene drosomycin, which is constitutively expressed in dUbc9 mutants in the absence of immune challenge. dUbc9-mediated drosomycin expression requires Dorsal and Dif. Although both studies are clear in concluding that Ubc9/Lesswright appears to function upstream of Cactus and Dorsal/Dif, the specific target is not yet known. Wild-type Ubc9/Lesswright hold the Toll pathway in check, and could target Cactus, Dorsal/Dif or another upstream component in the pathway (Huang, 2005; Chiu, 2005).

LIM-kinase1

The BMP receptor Wishful thinking (Wit) is required for synapse stabilization. In the absence of BMP signaling, synapse disassembly and retraction ensue. Remarkably, downstream Smad-mediated signaling cannot fully account for the stabilizing activity of the BMP receptor. LIM Kinase1 (LIMK1)-dependent signaling has been identified as a second, parallel pathway that confers the added synapse-stabilizing activity of the BMP receptor. LIMK1 binds a region of the Wit receptor that is necessary for synaptic stability but is dispensable for Smad-mediated synaptic growth. A genetic analysis demonstrates that LIMK1 is necessary, presynaptically, for synapse stabilization, but is not necessary for normal synaptic growth or function. Furthermore, presynaptic expression of LIMK1 in a wit or mad mutant significantly rescues synaptic stability, growth, and function. LIMK1 localizes near synaptic microtubules and functions independently of ADF/cofilin, highlighting a novel requirement for LIMK1 during synapse stabilization rather than actin-dependent axon outgrowth (Eaton, 2005).

Lkb1/PAR-4

The PAR-4 and PAR-1 kinases are necessary for the formation of the anterior-posterior (A-P) axis in Caenorhabditis elegans (Kemphues, 1988; Watts, 2000; Guo, 1995). PAR-1 is also required for A-P axis determination in Drosophila. The Drosophila par-4 homologue, lkb1, is required for the early A-P polarity of the oocyte, and for the repolarization of the oocyte cytoskeleton that defines the embryonic A-P axis. LKB1 is phosphorylated by PAR-1 in vitro, and overexpression of LKB1 partially rescues the par-1 phenotype. These two kinases therefore function in a conserved pathway for axis formation in flies and worms. lkb1 mutant clones also disrupt apical-basal epithelial polarity, suggesting a general role in cell polarization. The human homologue, LKB1, is mutated in Peutz-Jeghers syndrome (Hemminki, 1998; Jenne, 1998) and is regulated by prenylation and by phosphorylation by protein kinase A (Collins, 2000; Sapkota, 2001). Protein kinase A phosphorylates Drosophila LKB1 on a conserved site that is important for its activity. Thus, Drosophila and human LKB1 may be functional homologues, suggesting that loss of cell polarity may contribute to tumour formation in individuals with Peutz-Jeghers syndrome (Martin, 2003).

Male-specific lethal 3

The male-specific-lethal (MSL) proteins in Drosophila melanogaster serve to adjust gene expression levels in male flies containing a single X chromosome to equal those in females with a double dose of X-linked genes. Together with noncoding roX RNA, MSL proteins form the 'dosage compensation complex' (DCC), which interacts selectively with the X chromosome to restrict the transcription-activating histone H4 acetyltransferase MOF (Males-absent-on-the-first) to that chromosome. MSL3 is essential for the activation of MOF's nucleosomal histone acetyltransferase activity within an MSL1-MOF complex. By characterizing the MSL3 domain structure and its associated functions, it has been found that the nucleic acid binding determinants reside in the N terminus of MSL3, well separable from the C-terminal MRG signatures that form an integrated domain required for MSL1 interaction. Interaction with MSL1 mediates the activation of MOF in vitro and the targeting of MSL3 to the X-chromosomal territory in vivo. An N-terminal truncation that lacks the chromo-related domain and all nucleic acid binding activity is able to trigger de novo assembly of the DCC and establish an acetylated X-chromosome territory (Morales, 2005).

Neuropeptide F

Drosophila Neuropeptide F (Npf), a human NPY homolog, coordinates larval behavioral changes during development. The brain expression of npf is high in larvae attracted to food, whereas its downregulation coincides with the onset of behaviors of older larvae, including food aversion, hypermobility, and cooperative burrowing. Loss of Npf signaling in young transgenic larvae leads to the premature display of behavioral phenotypes associated with older larvae. Conversely, Npf overexpression in older larvae prolongs feeding, and suppresses hypermobility and cooperative burrowing behaviors. The neuropeptide F receptor (NPFR1) has also been characterized, and has been found to be expressed in a pair of dorsolateral neurons in the central brain and a small number of neurons in the subesophageal ganglion (Garczynski, 2002; Wen, 2005). The Npf system provides a new paradigm for studying the central control of cooperative behavior (Wu, 2003).

Pericentrin-like protein/cp309

Centrosomes consist of a pair of centrioles surrounded by an amorphous pericentriolar material (PCM). Proteins that contain a Pericentrin/AKAP450 centrosomal targeting (PACT) domain have been implicated in recruiting several proteins to the PCM. The only PACT domain protein in Drosophila (the Drosophila pericentrin-like protein [D-PLP]) is associated with both the centrioles and the PCM, and is essential for the efficient centrosomal recruitment of all six PCM components tested. Surprisingly, however, all six PCM components are eventually recruited to centrosomes during mitosis in d-plp mutant cells, and mitosis is not dramatically perturbed. Although viable, d-plp mutant flies are severely uncoordinated, a phenotype usually associated with defects in mechanosensory neuron function. The sensory cilia of these neurons are malformed and the neurons are nonfunctional in d-plp mutants. Moreover, the flagella in mutant sperm are nonmotile. Thus, D-PLP is essential for the formation of functional cilia and flagella in flies (Martinez-Campos, 2004).

Serpentine and vermiform

The function of tubular epithelial organs like the kidney and lung is critically dependent on the length and diameter of their constituting branches. Genetic analysis of tube size control during Drosophila tracheal development has revealed that epithelial septate junction (SJ) components and the dynamic chitinous luminal matrix coordinate tube growth. However, to date, the underlying molecular mechanisms controlling tube expansion have remained elusive. Two luminal chitin binding proteins, Serpentine and Vermiform, possessing predicted polysaccharide deacetylase activities (ChLDs) are required to assemble the cable-like extracellular matrix (ECM) and restrict tracheal tube elongation. Overexpression of native, but not of mutated, ChLD versions also interferes with the structural integrity of the intraluminal ECM and causes aberrant tube elongation. Whereas ChLD mutants have normal SJ structure and function, the luminal deposition of the ChLD requires intact cellular SJs. This identifies a new molecular function for SJs in the apical secretion of ChLD and positions ChLD downstream of the SJs in tube length control. serp and verm are not required for chitin synthesis or secretion but rather for its normal fibrillar structure. They are responsible for the N-deacetylation of chitin and conversion of chitin to chitosan, a polysaccharide composed of repeating glucosamine units; obtained by de-acetylation of chitin. The mutations also affect structural properties of another chitinous matrix, epidermal cuticle. In tracheal development, deposition of the chitin luminal matrix first promotes and coordinates radial tube expansion. It is proposed that the subsequent structural modification of chitin by chitin binding deacetylases selectively instructs the termination of tube elongation to the underlying epithelium (Wang, 2006; Luschnig, 2006).

Transient receptor potential

Drosophila transient receptor potential (Trp) serves dual roles as an essential cation channel during response to light and as a molecular anchor for the PDZ protein, INAD (inactivation no afterpotential D). Null mutations in trp cause impairment of visual transduction, mislocalization of INAD, and retinal degeneration. However, the impact of specifically altering Trp channel function is not known because existing loss-of-function alleles greatly reduce protein expression. In the current study the isolation of a set of new trp alleles is described, including trp¹⁴ with an amino acid substitution juxtaposed to the Trp domain. The trp¹⁴ flies stably express Trp and display normal molecular anchoring, but defective channel function. Elimination of the anchoring function alone in trp^Delta1272, has minor effects on retinal morphology whereas disruption of channel function causes profound light-induced cell death. This retinal degeneration is greatly suppressed by elimination of the Na⁺/Ca²⁺ exchanger, CalX, indicating that the cell death is due primarily to deficient Ca²⁺ entry rather than disruption of the Trp-anchoring function. The mechanism through which decreased Ca²⁺ influx causes cell death in trp appears to be due at least in part from increased rhodopsin-arrestin complexes that ensues from decreased Ca²⁺ (Wang, 2005b).

What's new in this edition [47] September 2006 continues:

Updates for previously included genes:
part 2/5 genes A-E | part 3/5 genes F-M | part 4/5 genes N-R | part 5/5 genes S-Z

Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.