BarH1 and BarH2

DEVELOPMENTAL BIOLOGY

Embryonic and Larval

See the embryonic expression pattern of B-H1 at the Berkeley Drosophila Genome Project Patterns of Gene Expression Site

Early expression is found in anterior segments, the labrium, maxilla and procephalic lobes at 5.5 to 6.5 hours into development. Other staining is seen in the mandible and procephalic lobe [Image]. Later, BarH1 and BarH2 are coexpressed in cells of the embryonic central and peripheral nervous systems. Positive cells are found in the procephalic lobe, antenna-maxillary complex, labium, hypopharynx and clypeolabrum [Images]. Expression in the brain is apparent. In each case the Bar proteins are expressed in a subset of neurons. In external sensory organs, their expression is marked in thecogens (glial cells) and neurons late in development (Higashijima, 1992b).

BarH1 and BarH2 are not only specifically coexpressed in the developing eye, but are also functionally required in R1/R6 prephotoreceptors and primary pigment cells in developing ommatidia (see The Drosophila Adult Ommatidium: Illustration and explanation with Quicktime animation). They are also essential for normal lens and pigment cell formation, and for the elimination of excess cells from mature ommatidia (Higashijima, 1992a).

Transient overexpression of BarH1 or BarH2 in the morphogenetic furrow of the developing eye produces a characteristic Bar-like eye malformation. It is suggested that Bar overexpression results in suppression of the anterior progression of the morphogenetic furrow and inhibition of reinitiation of normal ommatidial differentiation (Kojima, 1993).

Mutation of roughex perturbs cell fate determination. Many rux mutant clusters contain multiple boss-expressing cells. In some of these clusters, R8 cells are missing. There is also a reduction in the number of cells expressing bar and Seven-up. This may be due to errors in cell fate determination. Alternatively, the reduced number of cells expressing these markers may reflect cell death. Extensive cell death is seen in rux mutants beginning with the MF and extending to the posterior edge of the disc. In rux mutant discs, neuronal differentiation is delayed by approximately 6 hours of development (Thomas, 1994).

The simplest external sensory organ (es) found in the thorax and abdomen consists of a neuron and a set of two support cells. The glial cell (or thecogen) forms a sheath around the tip of a dendrite, whereas the outer support cells, the trichogen and tormogen, secrete cuticule structures. It is the thecogen cell (a glial type) that specifically expresses BarH1. The es neurons express both BarH1 and BarH2. These cells also produce Prospero and Cut, but not under control of Bar (Higashijima, 1992b).

Expression of Drosophila BarH1-H2 homeoproteins in developing dopaminergic cells and segmental nerve a (SNa) motoneurons

Barh1/h2 genes encode two related homeobox transcription factors (B-H1 and B-H2) previously shown to play essential roles in the formation and specification of the distal leg segments and in retinal neurogenesis. This study describes the restricted expression pattern of the B-H1/-H2 homeoprotein within the embryonic ventral nerve cord of Drosophila. B-H1/-H2 are specifically expressed in a subset of dopaminergic neurons, namely the unpaired ventral midline dopaminergic neuron, and in a subpopulation of laterally projecting motoneurons, i.e. the five motoneurons forming the segmental nerve a (SNa) branch. Using the GAL4-UAS system it is shown that B-H1/-H2Gal4 in combination with a membrane-targeted enhanced green fluorescent protein reporter line provides a powerful genetic tool reproducibly to label SNa motoneuron projections and terminals at the periphery, and their dendritic tree in the ventral nerve cord. Thus, the highly restricted expression pattern of the B-H1/-H2 homeoproteins and notably the related Gal4 driver represent powerful genetic tools to identify and study genes that control axon guidance, synaptogenesis or dendritic arborization within a small subpopulation of motoneurons identifiable from embryogenesis to late larval stages (Garces, 2006).

One line that showed highly restricted expression in subsets of cells in the VNC is an insertion in the Barh1 gene (denoted Barh1^lacZ). Barh1/h2 genes encode two related homeobox transcription factors (B-H1 and B-H2) previously shown to play essential roles in the formation and specification of the distal leg segments. In the embryo, B-H1 and B-H2 co-expression was described in intersegmental, dorsal epidermal cells and in some CNS cells. In the peripheral nervous system, they are expressed in es (external sensory) neurons and a fraction of their support cells where they are required for the correct subtype specification of es organs. In the VNC, Barh1 expression is first detected during late stage 12. The position and morphology of Barh1^lacZ-expressing cells suggested a neuronal identity. Using an antibody that recognizes both B-H1 and B-H2 it was found that the expression of B-H1/-H2 closely matches the Barh1^lacZ reporter expression in these cells. B-H1/-H2 expression in the VNC peaks at stage 14, when it is strongly expressed in exactly eight neurons per hemisegment, including the well-characterized ventral midline unpaired dopamine neuron [tyrosine hydroxylase (TH)-positive]. At this level in each hemisegment another TH- and Barh1- (and B-H1/-H2) positive cell was detected that lies more laterally. More dorsally, in the intermediate region of the VNC, a pair of cells expresses B-H1/-H2 within each hemisegment. Using the Barh1^lacZ reporter it was noted that Barh1 expression within this pair of cells varies considerably from hemisegment to hemisegment, frequently labeling only one cell or none at all. Finally, in the dorsal part of the VNC a group of three Barh1-positive (and B-H1/-H2) cells can be detected that lie at the lateral edge of the CNS. The possibility that one of these cells could be the dorsal lateral dopamine neuron was ruled out because no overlap between TH and Barh1 could be observed. Thus, in the VNC, Barh1 is expressed in a very small subset of post-mitotic cells including a subpopulation of dopaminergic neurons (Garces, 2006).

A key distinguishing trait of neurons is their axonal trajectory. To trace the trajectory of Barh1-positive neurons an available composite B-H1^Gal4 driver [denoted B-H1-GAL4.B4.5 or BN-GAL4 was used to express a membrane-targeted GFP [UAS-mEGFP^F]. In the VNC it was possible to detect B-H1^Gal4 expression starting at stage 13. It was first confirmed that the EGFP expression faithfully recapitulates the B-H1/-H2 expression pattern with the exception that the ventral unpaired dopaminergic neuron and the two other TH-positive cells described previously express B-H1/-H2 but not B-H1^Gal4. Another difference was that in some hemisegments, three cells located in the intermediate region of the VNC express B-H1^Gal4 whereas only two of three are consistently B-H1/-H2-positive. Since this difference is more prominent in early stage 14 embryos and tends to disappear in late stage 16 embryos, the presence of this ectopic cell (which lies in close proximity of the two other) could be due to the persistence of transgene expression and stability of the EGFP and thus reflects a transient expression of endogenous B-H1/-H2 in a common ganglion mother cell (Garces, 2006).

Using the B-H1^Gal4 driver the trajectory of B-H1/-H2-positive neurons was traced in late stage 16 and it was found that five of these cells are in fact motoneurons that fasciculate together before projecting into the periphery and specifically populate a same motor axon branch. In Drosophila abdominal hemisegments A₂–A₇, motor axons exit the CNS and project into the periphery along six nerves: the TN, the ISN and two SN branches. The main branch of the ISN innervates the dorsal and lateral body wall musculature. Axons in two branches of the ISN, ISNb and ISNd, defasciculate from the ISN to innervate distinct groups of ventral body wall muscles. Similarly, the primary branch of the SN, SNa, innervates a lateral muscle group, and axons on its minor branch, SNc, extend along SNa until a point at which they defasciculate and innervate ventral muscles. B-H1^Gal4-positive motor axons only extend in the SNa nerves and they can be visualized projecting onto muscles 21–24 (lateral transverse 1–4, LT1–4) and muscle 8 (segment border muscle, SBM ) and/or 5 (lateral oblique 1, LO1). Interestingly, no other cells in the CNS, whether glia or interneuron, express B-H1^Gal4. Together these data demonstrate that B-H1^Gal4-positive motor axons exclusively populate the SNa branch (Garces, 2006).

B-H1^Gal4 expression in the SNa nerve is maintained until the third larval stage when target muscle specificity and synaptic terminal morphology allow a precise identification of motoneurons. By comparing the GFP staining (from B-H1^Gal4::UAS-CD8-GFP) with anti-HRP immunofluorescence it was possible to visualize B-H1^Gal4-positive motor-axon projections on the field of muscles 21–24 but not toward muscles 5 and 8. Further comparison of the GFP and DLG [the predominantly post-synaptic structural protein mainly found in type Ib boutons] staining reveals that type Ib boutons are seen on each individual muscle 21–24 and were B-H1^Gal4-positive. HRP staining revealed that type II motoneuron extensions were not B-H1^Gal4-positive. In summary, these observations underline that the B-H1^Gal4 expression in late larval stages allows the visualization of a subset of SNa motoneurons supplying type Ib innervation to the 21–24 muscle field (Garces, 2006).

The SN has previously been defined as a nerve consisting exclusively of axons from motoneurons located in the same segment as the muscles they innervate. The precise mapping of motoneurons has shown, however, that only SNa and SNc are truly segmental nerves in that only these branches exclusively contain the axons of motoneurons from the same segment. It is these axons that exit the CNS through the segmental nerve root. Experiments combining the retrograde labeling of motoneurons with the analysis of clones generated by individual neuroblasts have provided solid evidence for grouping of motoneuron cell bodies in the CNS, often consisting of neurons that innervate operationally related muscles. It has been suggested that morphologically similar motoneurons arise from a common neuroblast, but that a single neuroblast may give rise to more than one morphological type. For example NB 2-2 produces two similar motoneurons. The cell bodies of these motoneurons lie in close vicinity in the VNC and their axons project to related muscles target, in this case muscles LT1–2. By contrast, NB 3-2 gives rise to two morphologically different sets of motoneurons. The first set of 3–4 motoneurons innervates the dorsal muscles DO3–4, DT1 and probably also muscle DO5. The second set of two motoneurons derived from NB 3-2 innervates muscle LT3 and probably also muscle. The detailed analysis of motoneurons expressing B-H1^Gal4 in combination with an anti B-H1/-H2 antibody has allowed identification of a group of three dorsal motoneurons located at the lateral edge of the VNC and a group of two motoneurons located more ventrally and medially. According to the previous tracing and mapping of motoneurons it can be hypothesized that (1) within the dorso-lateral group of SNa motoneurons two are in fact the motoneurons derived from NB 3-2 plus the motoneuron innervating SBM and/or LO1 (of unknown origin), and that (2) the two ventro-median SNa motoneurons are derived from NB 2-2. These observations underline that both subgroups of SNa motoneurons derived from two different neuroblasts specifically express B-H1^Gal4 and are B-H1/-H2 positive. As noted above, the lack of B-H1^Gal4 expression within the dopaminergic cells proved advantagous because only motoneurons projections can be unambiguously followed (Garces, 2006).

Motoneurons that innervate neighboring muscles have overlapping dendritic trees and this is even true for related motoneurons that are derived from different neuroblasts. Using the B-H1^Gal4 driver to express a membrane-targeted EGFP, it was observed that SNa motoneurons elaborate their dendrites in a specific region of the dorsal neuropile which lies lateral to the anterior commissure, as previously described by others using retrograde labeling of motoneurons. Because no other cells in the VNC – either interneurons or glia – express B-H1^Gal4, this Gal4 driver in combination with the membrane-targeted EGFP reporter line used [UAS-mEGFP^F] provides a powerful genetic tool to label SNa motoneurons reproducibly and to visualize their morphology. To illustrate that this Gal4 can be used for experiments aiming to manipulate SNa motoneurons genetically, a constitutively active form of the small GTPase RhoA [RhoA(V14)] was misexpressed in SNa motoneurons. Misexpression of RhoA(V14) using the UAS/Gal4 system in mushroom body neurons results in a reduction of the Calyx volume and dendritic complexity of these neurons. When UASRhoA(V14) is misexpressed (together with UAS-EGFP^F) using the B-H1^Gal4 as a driver, SNa motoneurons display a less elaborate dendritic arborization compared with controls. Furthermore, the position of SNa motoneuron cell bodies within the VNC is reproducibly affected (48 hemisegments analysed), as they appear as a single medial cluster in close apposition to the most lateral longitudinal interneuronal fascicule. This result shows that the B-H1^Gal4 line represents an efficient tool to functionally manipulate the SNa motononeuron population (Garces, 2006).

Moreover, as no other transcription factor or molecular marker has been previously reported to be specifically expressed within the SNa motoneuron subpopulation, the Bar-H1/-H2 genes will be very useful markers for further characterization of these neurons. Furthermore, the restricted expression pattern of both genes allows distinguishing molecularly between SNa and SNc motoneurons, which represent two related subpopulations of segmental motoneurons that innervate, respectively, a set of lateral and ventral somatic muscles. The Barh1^lacZ and notably the composite B-H1^Gal4 driver are thus powerful genetic tools in studies aiming to identify and investigate genes that control axon guidance, synaptogenesis and dendritic arborization within a very small subpopulation of motoneurons. As a standardized system for mapping neurons and their related neurites in the Drosophila embryonic VNC is emerging, the present work complements understanding of the partitioning of the neuropile and extends previous work which aims to investigate circuit formation in the CNS of Drosophila embryos and larvae (Garces, 2006).

Effects of Mutation or Deletion

Simultaneous deletion of Bar genes leads to irregularly fused, bulging ommatidia, greatly differing in the number of rhabdomeres. Thus Bar genes are required for proper eye morphogenesis (Higashijima, 1992a and Kojima, 1993).

A new segment polarity gene of Drosophila melanogaster, oroshigane (oro) was identified as a dominant enhancer of Bar (B). The B1 allele of the Bar locus is associated with a tandem duplication of the division 16A of the X chromosome and causes the overexpression of the Bar (B) gene. decapentaplegic expression in the morphogenetic furrow is abolished in the B background, and therefore morphogenetic furrow progression prematurely ceases resulting in the characteristic bar-shapped compound eye. hedgehog expression also fades 8 hours after heat induction of the Bar protein, indicating that hh is another target for inhibition by B. Since the Bar protein is required for R1, R6 and primary pigment cell differentiion behind the furrow, the overexpressed B protein apparently interferes with furrow progression by inhibiting dpp expression in the furrow and hedgehog expression just behind the furrow. Overexpression of the Bar protein has little deleterious effect on differentiation of photoreceptor clusters that have already started to develop behind the morphogenetic furrow. Failure of morphogenetic furrow progression likely triggers programmed cell death in the undifferentiated cells ahead of the morphogenetic furrow (Epps, 1997).

oro is a recessive embryonic lethal, and homozygous oro embryos show variable substitution of denticles for naked cuticle. These patterns are distinctly similar to those of hedgehog and wingless mutant embryos, which indicates that oro functions in determining embryonic segment polarity. oro works downstream of hedgehog but upstream of dpp to enhance the Bar phenotypes. Although dpp expression is reduced in oro heterozygotes, hh expression remains the same as that found in wild-type discs. Evidence that oro function is involved in Hh signal transduction during embryogenesis is provided by its genetic interactions with the segment polarity genes patched and fused. ptcIN is a dominant suppressor of the oro embryonic lethal phenotype, suggesting a close and dose-dependent relationship between oro and ptc in Hh signal transduction. oro function is also required in imaginal development. The oro1 allele significantly reduces decapentaplegic (but not hh) expression in the eye imaginal disc. oro enhances the fused1 wing phenotype in a dominant manner. Based upon the interactions of oro with hh, ptc, and fu, it is proposed that the oro gene plays important roles in Hh signal transduction (Epps, 1997).

In the developing Drosophila eye, BarH1 and BarH2, paired homeobox genes expressed in R1/R6 outer photoreceptors and primary pigment cells, are essential for normal eye morphogenesis. BarH1 was ectopically expressed under the control of the sevenless enhancer (sev-BarH1). The sev enhancer drives gene expression strongly, not only in R7 precursors but also in R3/R5 and cone cell precursors. Evidence is presented that sev-BarH1 causes two types of cone cell transformation: transformation of anterior/posterior cone cells into outer photoreceptors and transformation of equatorial/polar cone cells into primary pigment cells. The ectopic primary pigment cells are partially similar in morphology to cone cells. sev-BarH1 represses the endogenous expression of the rough homeobox gene in R3/R4 photoreceptors, while the BarH2 homeobox gene is activated by sev-BarH1 in an appreciable fraction of extra outer photoreceptors. In primary pigment cells generated by cone cell transformation, the expression of cut, a homeobox gene specific to cone cells, is completely replaced with that of Bar homeobox genes. Extra outer photoreceptor formation is either suppressed or enhanced, respectively, by reducing the activity of Ras/MAPK signaling or by dosage reduction of yan, a negative regulator of the pathway, suggesting interactions between Bar homeobox genes (cell fate determinants) and Ras/MAPK signaling in eye development. It is concluded that cone cell precursors may adopt four different cell fates: an outer photoreceptor fate, a primary pigment cell fate, a cone cell fate, or the fate of disappearance f from ommatidia (X-cell fate). Cone cell precursors appear to be divided into two subgroups with respect to sensitivity to sev-BarH1: either anterior/posterior or equatorial/polar cone cell precursors. sev-BarH1 causes transformation of a fraction of anterior/posterior cone cells into outer photoreceptors partially expressing R1/R6-specific genes and also causes the transformation of a fraction of equatorial/polar cone cells into primary pigment cells; this suggests that BarH1 serves as a determinant of R1/R6 and primary pigment cell fates in normal eye development (Hayashi, 1998).

The progression of the morphogenetic furrow in the developing Drosophila eye is an early metamorphic, ecdysteroid-dependent event. Although Ecdysone receptor-encoded nuclear receptor isoforms are the only known ecdysteroid receptors, it has been shown that the Ecdysone receptor gene is not required for furrow function. DHR78, which encodes another candidate ecdysteroid receptor, is also not required. In contrast, zinc finger-containing isoforms encoded by the early ecdysone response gene Broad-complex regulate furrow progression and photoreceptor specification. br-encoded Broad-complex subfunctions are required for furrow progression and proper R8 specification, and are antagonized by other subfunctions of Broad-complex. There is a switch from Broad complex Z2 to Z1 zinc-finger isoform expression at the furrow that requires Z2 expression and responds to Hedgehog signals. These results suggest that a novel hormone transduction hierarchy involving an uncharacterized receptor operates in the eye disc (Brennan, 2001).

Bar is a dominant mutation causing premature arrest of the furrow, which results in the deep anterior nick in the adult eye. Since Bar has the dominant effect of stopping the furrow early, one might expect loss-of-function mutations at other loci that normally act to promote furrow progression to be genetic enhancers of Bar and loss-of-function mutations in genes that normally antagonize the furrow to act as genetic suppressors of Bar. Thus, genetic interactions between BR-C sub loci and Bar were examined. Mutants defective for different BR-C subfunctions display unexpected heterogeneity in their genetic interactions with Bar, suggesting that the role of the BR-C in the regulation of furrow function might be complex. BR-C has several recessive lethal complementation groups that correspond to mutations that remove the function of all or individual zinc finger-containing isoforms subgroups. npr1 mutations lack all function, whereas rbp, br and 2Bc mutant groups correspond to the loss of Z1-, Z2-, and Z3-containing isoforms, respectively. Both npr1/Bar and br/Bar eyes are significantly smaller than +/Bar, indicating a dominant enhancement of the Bar furrow-stop phenotype, consistent with the earlier reports that the BR-C is required for furrow progression. However, br/Bar eyes are smaller than npr1/Bar, suggesting that the BR-C might encode isoforms that act antagonistically during furrow progression, so that the effect of losing isoforms that positively regulate furrow progression is more severe than losing all isoforms. This idea is supported by the observation that rbp/Bar and 2Bc/Bar eyes are larger than +/Bar, suppressing the phenotype, and possibly representing furrow-antagonistic functions of rbp- or br-encoded BR-C isoforms (Brennan, 2001).

Hemizygous males of all BR-C mutant groups survived through the third instar: the eye discs of these males displayed defects consistent with the genetic interactions with Bar. npr1/Y discs show ommatidial disorganization, and signs of furrow failure, including mature ommatidial clusters at the furrow. br/Y discs show a much more dramatic failure of furrow progression, as well as ommatidial disorganization. rbp/Y and 2Bc/Y discs do not show any defects. While rbp does interact strongly with Bar it shows no eye disc defect alone -- it may be that rbp is a redundant function (Brennan, 2001).

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date revised: 30 May 2008

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