buttonless: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

Gene name - buttonless

Synonyms -

Cytological map position - 94B1-94B11

Function - transcription factor

Keywords - mesodermal, axon guidance

Symbol - btn

FlyBase ID:FBgn0014949

Genetic map position -

Classification - homeodomain protein

Cellular location - nuclear

NCBI link: Entrez Gene

buttonless orthologs: Biolitmine
Recent literature
Kokotovic, T., Lenartowicz, E. M., Langeslag, M., Ciotu, C. I., Fell, C. W., Scaramuzza, A., Fischer, M. J. M., Kress, M., Penninger, J. M. and Nagy, V. (2022). Transcription factor Mesenchyme Homeobox Protein 2 (MEOX2) modulates nociceptor function. FEBS J. PubMed ID: 35029322
Mesenchyme homeobox protein 2 (MEOX2) is a transcription factor involved in mesoderm differentiation, including development of bones, muscles, vasculature and dermatomes. Dysregulation was identified of MEOX2 in fibroblasts from Congenital Insensitivity to Pain (CIP) patients, and it was confirmed that buttonless, the Drosophila homologue of MEOX2, plays a role in nocifensive responses to noxious heat stimuli. To determine the importance of MEOX2 in the mammalian peripheral nervous system, a Meox2 heterozygous (Meox2(+/-)) mouse model was used to characterize its function in the sensory nervous system, and more specifically, in nociception. MEOX2 is expressed in the mouse dorsal root ganglia (DRG) and spinal cord, and localizes in the nuclei of a subset of sensory neurons. Functional studies of the mouse model, including behavioral, cellular and electrophysiological analyses, showed altered nociception encompassing impaired action potential initiation upon depolarization. Mechanistically, decreased expression was noted of Scn9a and Scn11a genes encoding Na(v) 1.7 and Na(v) 1.9 voltage gated sodium channels, respectively, that are crucial in subthreshold amplification and action potential initiation in nociceptors. Further transcriptomic analyses of Meox2(+/-) DRG revealed downregulation of a specific subset of genes including those previously associated with pain perception, such as PENK and NPY. Based on these observations, a novel role of MEOX2 in primary afferent nociceptor neurons is proposed for the maintenance of a transcriptional program required for proper perception of acute and inflammatory noxious stimuli.

buttonless is a novel homeodomain gene expressed in only one type of mesodermal cell during Drosophila development. Such cells, the dorsal median (DM) cells, are arranged as a single pair within each segment along the dorsal midline just above the central nervous system. btn mutation specifically eliminates the DM cells and this genetic ablation reveals a requirement for DM cells as cellular cues for axonal guidance during transverse nerve outgrowth as well as bifurcation of a particular nerve: the median nerve (Chiang, 1994).

By stage 11 (the extended germ band at 5.5 to 6 hours of development), in situ hybridization can detect BTN mRNA in individual cells; this mRNA is found in a group of two to four midline cells in each of the three thoracic segments and in the first seven abdominal segments. During germ-band retraction, the bodies of these cells remain at the midline, but the cells begin to extend lateral processes, until by stage 14 the cells appear well differentiated and their processes extend beyond the ventral cord to the sites of muscle attachment. The number of cells expressing btn is reduced from four to two per segment by an as yet unresolved mechanism that could involve either cell fusion or cell death. In contrast to anterior DM cells, which display a characteristic oval shape with lateral processes, the cell bodies of posterior DM cells form a triangle with processes that extend anteriorly and laterally from the vertices (Chiang, 1994). By stage 14, DM cell horizontal processes extend to and insert into epidermal muscle attachment sites. DM cells have been shown to express Neuroglian (Bieber, 1989) and extracellular matrix proteins such as laminin, Glutactin and collagen IV (Olson, 1990).

A P element insertion in the btn gene was used to mark DM cells. This marker reveals that btn is required for DM cell differentiation and that the inital commitment to the DM cell fate occurs in the absence of btn function as evidenced by normal initiation of btn reporter expression in btn mutant embryos (Chiang, 1994).

Cellular studies of several insects, all larger than Drosophila, provide clues regarding potential function of the Drosophila DM cells. The muscle pioneer cells of the grasshopper have a similar function and distribution as Drosophila DM cells, but appear to serve as a site of recruitment for other mesodermal cells that eventually form the transverse muscle, a muscle not seen in Drosophila. In Manduca, a similar group of cells appears during development and is thought to prefigure the growth of the transverse nerve, which courses laterally toward the periphery in each segment.

In Drosophila, as in Manduca, the median nerve appears to grow posteriorly along the midline and then bifurcates to contribute to the transverse nerve, which also has been shown to carry axons of identified neurosecretory cells (Zitnan, 1993). It is clear that the median nerve in Drosophila bifurcates at the point where it encounters the DM cell bodies and that the transverse nerve precisely follows the path of the DM cell process. Transverse nerves are absent in btn mutants. By stage 16 of development, abnormally long and thick axon bundles expressing Fasciclin II can be seen in mutant flies, extending along the midline at the dorsal surface of the ventral cord. It is presumed that these bundles result from outgrowth and fasiculation of axons that contribute to the median nerve in multiple segments (Chiang, 1994).

The method used to isolate btn is of interest because it provides a possible clue as to the nature of DM cells. btn was isolated as a complementary DNA (cDNA) by employing a hybridization probe (in this case, a degenerate 23-base oligonucleotide corresponding to a widely conserved region within the third helix of the homeodomain). The library screened with this probe derives from a cultured Drosophila cell line called shibire (originally established from shibire mutant embryos) in which expression of the Ultrabithorax homeotic protein was experimentally induced. Of the eight homeodomain coding sequences isolated by this procedure, two represent the gene btn. What all this means, is that one of the RNA species present in this particular cell line is likely to represent BTN messenger RNA (Chiang, 1994).

The shibire cells from which btn complementary DNA was identified display a monopolar or bipolar cell morphology with extended processes that resemble those of DM cells. BTN mRNA is normally expressed in the shibire cell line and does not require transcriptional activation by UBX protein. Given the exquisite specificity of btn expression in the embryo and the obvious morphological similarities between DM cells and the shibire cells, it is suggested that the shibire cell line may be representative of DM cells in embryos (Chiang, 1994).

Fasciclin II, expressed on axons of the median and transverse nerves, may interact with Neuroglian, expressed on the surfaces of DM cell processes to promote adhesion and guide axon outgrowth. Loss of this interaction in btn mutants might account for the abnormal path and thickness of the median nerve, since in the absence of Neuroglian the homophilic adhesion properties of Fasciclin II might lead to abnormal fasciculation of axons expressing the Fas II protein (Chiang, 1994).


transcript length - 600-700 bases

Exons - 1


Amino Acids - 158

Structural Domains

The BTN protein is the smallest reported homeodomain protein (Chiang, 1994).


Outside the homeodomain, the BTN protein shares no significant homology with other proteins. The homeodomain is most closely related to a divergent family of vertebrate homeobox genes sharing amino acid identities of 77-78% with Mox-1 and Mox-2 genes in the mouse (Candia, 1992), the Gax gene in the rat (Gorski, 1993) and the Xelmox2 gene in Xenopus (Candia, 1992). All these homeodomains, including that of BTN, contain a lysine residue at position 3. The majority of other homeodomains carry an arginine residue at this position. The Arg makes a specific contact with the second of four bases within the core of the homeodomain recognition site (TAAT) (Chiang, 1994).

Two mouse genes, Mox-1 and Mox-2 define a novel homeobox gene family by sequence, genomic structure and expression pattern, probably one involved in mesodermal regionalization and somitic differentiation. Mox-1 is genetically linked to the keratin and Hox-2 genes of chromosome 11, while Mox-2 maps to chromosome 12. At primitive streak stages (approximately 7.0 days post coitum), Mox-1 is expressed in mesoderm lying posterior of the future primordial head and heart. It is not expressed in neural tissue, ectoderm, or endoderm. Mox-1 expression may therefore define an extensive 'posterior' domain of embryonic mesoderm before, or at the earliest stages of, patterning of the mesoderm and neuroectoderm by the Hox cluster genes. Between 7.5 and 9.5 days post coitum, Mox-1 is expressed in presomitic mesoderm, epithelial and differentiating somites (dermatome, myotome and sclerotome) and in lateral plate mesoderm. In the body of midgestation embryos, Mox-1 signal is restricted to loose undifferentiated mesenchyme. Mox-1 signal is also prominent over the mesenchyme of the heart cushions and truncus arteriosus, arising from epithelial-mesenchymal transformation and over a limited number of craniofacial foci of neural crest-derived mesenchyme that are associated with muscle attachment sites. The expression profile of Mox-2 is similar to, but different from, that of Mox-1. For example, Mox-2 is apparently not expressed before somites form. Once they do form it is then expressed over the entire epithelial somite, but during somitic differentiation, Mox-2 signal rapidly becomes restricted to sclerotomal derivatives. The expression patterns of these genes suggest regulatory roles for Mox-1 and Mox-2 in the initial anterior-posterior regionalization of vertebrate embryonic mesoderm and, in addition, in somite specification and differentiation (Candia, 1992).

Mesoderm specific expression of Xenopus Mox-2 (X. Mox-2) expression begins during gastrulation. X. Mox-2 is expressed in undifferentiated dorsal, lateral and ventral mesoderm in the posterior of neurula/tailbud embryos, with expression more anteriorly detected in the dermatomes. In the tailbud tadpole, X. Mox-2 is expressed in tissues of the tailbud itself that represent a site of continued gastrulation-like processes resulting in mesoderm formation. X. Mox-2 is not expressed in the marginal zone of blastula, nor in the dorsal lip of gastrula, nor midline tissues (i.e. prospective notochord). Treatments that affect mesodermal patterning during embryonic development (including LiCl and ultraviolet light, and injection of mRNAs encoding BMP-4, or dominant negative activin and FGF receptors) produce changes in X. Mox-2 expression consistent with the types of tissues affected by these manipulations. X. Mox-2 expression is induced more in animal caps treated with FGF than those treated with activin. Together with the fact that X. Mox-2 activation in animal caps requires protein synthesis, these data suggest that X. Mox-2 is involved in initial mesodermal differentiation, downstream of molecules affecting mesoderm induction and determination such as Brachyury and goosecoid, and upstream of factors controlling terminal differentiation such as MyoD and myf5. Therefore X. Mox-2 is another useful marker for understanding the formation of mesoderm in amphibian development (Candia, 1995).

Adult vascular smooth muscle cells dedifferentiate and reenter the cell cycle in response to growth factor stimulation. Expression of a diverged homeobox gene, Gax, is largely confined to the cardiovascular tissues of the adult. In quiescent adult rat vascular smooth muscle cells, GAX mRNA levels are down-regulated as much as 15-fold within 2 h when these cells are induced to proliferate with platelet-derived growth factor (PDGF) or serum growth factors. This reduction in GAX mRNA is transient, with levels beginning to rise between 8 and 24 h after mitogen stimulation, returning to near normal by 24 to 48 h. The Gax down-regulation is dose dependent and can be correlated with the mitogen's ability to stimulate DNA synthesis. PDGF-AA, a weak mitogen for rat vascular smooth muscle cells, does not affect Gax transcript levels, while PDGF-AB and -BB, potent mitogens for these cells, are nearly as effective as fetal bovine serum. The removal of serum from growing cells induces Gax expression fivefold within 24 h. These data suggest that Gax is likely to have a regulatory function in the G0-to-G1 transition of the cell cycle in vascular smooth muscle cells (Gorski, 1993).

buttonless: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 22 March 2022 

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