FMRFamide: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | References

Gene name - FMRFamide

Synonyms -

Cytological map position - 46C1--46C2

Function - Neuropeptide

Keywords - Brain, CNS, hormones

Symbol - FMRFa

FlyBase ID: FBgn0000715

Genetic map position - 2-[59].

Classification - FMRFamide-related

Cellular location - cytoplasmic and secreted

NCBI links: Entrez Gene

FMRFamide orthologs: Biolitmine
Recent literature
Bivik, C., Bahrampour, S., Ulvklo, C., Nilsson, P., Angel, A., Fransson, F., Lundin, E., Renhorn, J. and Thor, S. (2015). Novel genes involved in controlling specification of Drosophila FMRFamide neuropeptide cells. Genetics [Epub ahead of print]. PubMed ID: 26092715
The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification. In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, out of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell; neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification, makes FMRFa a valuable readout for addressing many aspects of neural development. To this end, this paper describes a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as a read-out. Systems identified in this screen included Polycomb group and Hox genes, columnar and segment polarity genes, temporal and NB identity genes, chromatin modification factors, cell fate determinants, axonal retrograde transport/BMP and Notch signaling factors, asymmetric cell division factors, chromosome condensation, cytokinesis, proteolysis and cell cycle factors, and RNA processing and Toll, Wnt and EGFR signaling factors. Novel alleles were isolated for previously known FMRFa regulators, confirming the validity of the screen. In addition, novel essential genes were identified, including several with previously undefined functions in neural development. This identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.
Berndt, A. J., Othonos, K. M., Lian, T., Flibotte, S., Miao, M., Bhuiyan, S. A., Cho, R. Y., Fong, J. S., Hur, S. A., Pavlidis, P. and Allan, D. W. (2020). A low affinity cis-regulatory BMP response element restricts target gene activation to subsets of Drosophila neurons. Elife 9. PubMed ID: 33124981
Retrograde BMP signaling and canonical pMad/Medea-mediated transcription regulate diverse target genes across subsets of Drosophila efferent neurons, to differentiate neuropeptidergic neurons and promote motor neuron terminal maturation. How a common BMP signal regulates diverse target genes across many neuronal subsets remains largely unresolved, although available evidence implicates subset-specific transcription factor codes rather than differences in BMP signaling. This study examined the cis-regulatory mechanisms restricting BMP-induced FMRFa neuropeptide expression to Tv4-neurons. pMad/Medea bind at an atypical, low affinity motif in the FMRFa enhancer. Converting this motif to high affinity caused ectopic enhancer activity and eliminated Tv4-neuron expression. In silico searches identified additional motif instances functional in other efferent neurons, implicating broader functions for this motif in BMP-dependent enhancer activity. Thus, differential interpretation of a common BMP signal, conferred by low affinity pMad/Medea binding motifs, can contribute to the specification of BMP target genes in efferent neuron subsets.


Hormonal structure and function have been evolutionarily conserved to a remarkable degree: this is true for insects as a class as well as a wide variety of other metazoans. At least five insect peptide hormones are known to have been structurally and/or functionally conserved: prothoracicotropic hormone and bombyxin (induce release of ecdysteroid by the prothoracic glands) allatotropin, allatostatin (regulate production of juvenile hormone by the corpora allata), and diuretic hormone. None of these have been cloned in Drosophila, but use of antibodies against the hormones of other insect species reveals hormone presence in distinct sets of cells in the central nervous system of Drosophila larvae, pupae, and adults. Brain neurons synthesizing bombyxin, PTTH (see Bombyx and Manduca prothoracicotropic hormone), and DH are in strikingly similar positions when compared with their lepidopteran counterparts, indicating that at least some Drosophila neuroendocrine cells are homologous to those of lepidopterans. Allatotropin and allatostatin-immunopositive neurons of Drosophila differ from those of lepidopterans, but many of them are identical to neurons that express the FMRFamide gene. Antibodies to bombyxin, PTTH, allatostatin, and DH also stain axons and axon terminals in the neurohemal part of the ring gland, and all tested antibodies except that against bombyxin show positive reaction in the neurohemal area of the ventral ganglion (Zitnan, 1993).

The Drosophila FMRFamide gene was identified by its homology to a gene first sequenced in the marine snail Aplysia. FMRFamide was first purified as a cardioregulatory tetrapeptide from the central nervous system of the clam. In molluscs, it modulates both cardiac output and the actions of neurons, as well as regulating evoked muscle tension. In cattle, two peptides immunoreactive to a related lobster hormone have been identified; the cattle proteins have anti-analgesic properties. FMRFamide genes of Drosophila and Aplysia share sequence homologies with mammalian genes encoding the opioid peptide and corticotrophin-releasing factor. To confuse matters, multiple RFamide-containing peptides are present in Drosophila, encoded by three genes: drosulfakinin (Nichols, 1988 and 1992b), dromyosuppressin, and FMRFamide (Taghert, 1992 and references).

There is a remarkably reproducable distribution of FMRFamide neuropeptide in identifiable neuroendrocrine cells and interneurons in Drosophila and other insects. The expression of the FMRFamide gene is a cell specific phenotype confined to about 30 regions within the larval CNS. Among this set of neurons, there is a reproducible and systematic variation in the intensity of hybridization signals and in the time during development when transcripts are first detectable (Schneider, 1993a).

Representative of the distribution of products of the FMRFamide gene is the distribution of DPKQDFMRFamide, one of the 13 peptides coded for by the FMRFamide gene. The earliest observed DPKQDFMRFamide is found in neural tissue from stage 16 embryos. Faint staining is observed in one cell in the subesophageal ganglion from which an immunoreactive fiber projects into the ventral ganglion and to one cell in each of the three thoracic ganglia. In larval neural tissue, staining is observed in two bilaterally paired cells in the subesophageal ganglia (SE2) and SV, and in bilaterally paired cells in each of the thoracic ganglia (T1, T2 and T3). Three bilaterally paired cells in the superior protocerebrum (SP1, SP2 and SP3) stain for DPKQDFMRFamide. In pupae, SP1 remains stained, and a new bilaterally paired cell in the lateral protocerebrum (LP1) stains. The T1-3 staining remains and an additional bilaterally paired cell in the second thoracic ganglion (T2dm) stains as well as a bilaterally paired cell in the abdominal ganglion (A8). In the adult, staining is apparent is SP1, SP2, SP3, LP1, cells of the optic lobe (OL2), cells of the subeosophageal ganglion (SV and SE2), cells in the three thoracic ganglia (T1-3 and T2dm) and in the abdominal ganglion. These cells are a subset of cells that stain with an FMRFamide antiserum that stains for the polypeptide precursor. These data suggest that the FMRFamide polypeptide precursor undergoes differential processing to produce DPKQDFMRFamide immunoreactive material in a limited number of cells expressing the FMRFamide precursor (Nichols, 1995a).

What is the cellular target of FMRFamide? Is it a serpentine seven pass transmembrane receptor, the classic targets of peptide hormones, or is there another target? Although FMRFamides constitute a major class of invertebrate peptide neurotransmitters, the molecular structure of their receptors has not yet been identified. In neurons of the snail Helix aspersa, as well as in the bursting and motor neurons of Aplysia, FMRFamide induces a fast excitatory depolarizing response due to direct activation of an amiloride-sensitive Na+ channel. A complementary DNA has been isolated from Helix nervous tissue; when expressed in Xenopus oocytes, it encodes an FMRFamide-activated Na+ channel (FaNaCh) that can be blocked by amiloride. The protein shares a very low sequence identity with epithelial Na+ channel subunits and C. elegans degenerins, but it displays the same overall structural organization. This is the first characterization of a peptide-gated ionotropic receptor (Lingueglia, 1995).

Another study implicates G protein coupled receptors as mediators of FMRFamide signals. PDVDHVFLRFamide acts in the locust oviduct. Inhibitory peptides and stimulatory peptides share a single receptor by having the same binding sequence, VFLRFamide, but are able to produce opposite muscle responses due to the differences in activation sites. The receptors for the inhibitory and stimulatory FMRFamide-related peptides (FaRPs) are coupled with G proteins and both inhibitory and excitatory effects of FaRPs on locust oviduct occur through the activation of G proteins. It is very likely that the receptor is coupled with two different G proteins. The activation of one is responsible for the inhibitory effect and the activation of the other is responsible for the stimulatory effect (Wang, 1995b).


Transcript size - 1.7 kb

Bases in 5' UTR - 106

Exons - 2

Bases in 3' UTR - 275


Amino Acids - 347

Structural Domains

The Drosophila FMRFamide neuropeptide gene contains two exons separated by an intron of approximately 2.5 kilobase pairs. The promoter region contains a TATA box 30 nucleotides upstream from a consensus transcription start site. The open reading frame (encoding the neuropeptide precursor) begins with the first nucleotide of exon II. The precursor protein contains 5 copies of DPKQDFMRFamide, as well as 8 additional amidated peptides exhibiting varying degrees of structural relatedness. The Drosophila DPKQDFMRFamide gene and the Aplysia FMRFamide gene are ancestrally related; however, peptides display a higher degree of homology within a species than between species, suggesting intragenic concerted evolution of these neuropeptides (Chin, 1990, Nambu, 1988, Schneider, 1988 and 1990).

FMRFamide: Evolutionary Homologs | Regulation | Developmental Biology | References

date revised: 19 MAR 97 

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