ham is expressed in a ventral patch in the cephalic region of the embryo from stage 5 and continues to be expressed in the cephalic region through stage 15. It is expressed in the developing PNS from stage 11 through 15 and shows transient expression in each PNS cluster. The Ham protein has the same expression profile as the mRNA and has a nuclear localization. In the ESOP lineage, it is first expressed in the IIIB cell and is inherited by both the ES neuron and glia daughter cells after IIIB division. Although Ham quickly disappears in the differentiating glia, it continues to be expressed by the ES neuron during initial dendrite extension, indicating that it may be active both pre- and postmitotically in these neurons. Ham levels become undetectable as further dendrite elaboration occurs. This expression pattern is consistent with the notion that Ham is required for proper cell fate specification of the IIIB lineage, and is required for the dendritic morphogenesis of the ES neuron (Moore, 2002).
For a complete and accurate sampling of sensory or presynaptic input, neuronal ensembles can organize as tiled systems, with the dendritic fields of like neurons partitioning a receptive area much like tiles covering a floor. Understanding how dendrites establish their territory is central to elucidating how neuronal circuits are built. Signaling between dendrites is thought to be important for defining their territories; however, the strategies by which different types of dendrites communicate are poorly understood. Two classes of Drosophila peripheral da sensory neurons, the class III and class IV neurons, provide complete and independent tiling of the body wall. By contrast, dendrites of class I and class II neurons do not completely tile the body wall, but they nevertheless occupy nonoverlapping territories. To address the generality of tiling and also its mechanistic basis, a strain of flies was generated with all class IV neurons marked with Enhanced Green Fluorescent Protein (EGFP) to facilitate live imaging of tiling dendritic arbors. By developing reagents to permit high-resolution studies of dendritic tiling in living animals, it was demonstrated that isoneuronal and heteroneuronal class IV dendrites engage in persistent repulsive interactions. In contrast to the extensive dendritic exclusion shown by class IV neurons, duplicated class III neurons shows repulsion only at their dendritic terminals. Supernumerary class I and class II neurons innervated completely overlapping regions of the body wall, and this finding suggests a lack of like-repels-like behavior. These data suggest that repulsive interactions operate between morphologically alike dendritic arbors in Drosophila. Further, Drosophila da sensory neurons appear to exhibit at least three different types of class-specific dendrite-dendrite interactions: persistent repulsion by all branches, repulsion only by terminal dendrites, and no repulsion (Grueber, 2003).
The growth of dendrites after cell ablation suggests that repulsive signaling is required for tiling. If these signals are communicated between dendrites, then overproduction of da neurons should lead to ectopic partitioning of territories. To test this idea, an overproduction of class IV neurons was induced by introducing mutations in the hamlet (ham) gene into a ppk-EGFP genetic background (EGFP driven by the pickpocket promoter. ham is required for the specification of external sensory (es) neurons, and loss of ham leads to es neurons adopting a multidendritic neuron fate. In a ham background, doubling of v′ada, but not of the other two abdominal class IV neurons was frequently observed. In each case (n = 11), the morphology of these two adjacent neurons was similar, and, in ten of these cases, dendrites projected to, and terminated within, distinct domains of the body wall. One case was observed in which the major trunks of the two adjacent neurons clearly projected to an overlapping region, which the finer branches partitioned into nonoverlapping subdomains. In response to the extra neuron, the dendritic field of vdaB was restricted to a more ventral region of the body wall. The ectopic partitioning of the body wall induced by overproduction of class IV neurons strongly suggests that repulsive dendritic interactions occur between dendrites of like neurons (Grueber, 2003).
The class I, II, and III neurons are organized differently from the class IV neurons; they have dendrites that are either not normally in close apposition (classes I and II) or provide a low-density coverage of the body wall (class III). It was asked whether these neurons might show exclusion if produced in excess. Supernumerary neurons were produced by making MARCM clones by using big brain (bib) or ham mutations, both of which lead to overproduction of neurons. Duplications of class I, II, and III neurons were observed in ham clones and duplication of class I neurons was observed in bib clones. In contrast to the dendritic avoidance exhibited by duplicated class IV neurons, duplicated class I neurons and class II neurons innervated overlapping regions of the body wall in each case examined. Although these dendrites did not clearly fasciculate, they intermixed very extensively, and often it was not possible to distinguish between the arbors of the two neurons. Class III neurons duplicated in ham MARCM clones behave much like the class I and II neurons in that their major trunks overlap extensively and often extend along the same direction since they cover identical territories of the epidermis. Extensive overlap was not observed, however, among the short terminal extensions of the class III neurons. It is therefore possible that these short branches contribute to the dendritic exclusion normally observed among class III neurons (Grueber, 2003).
Results from several recent studies suggest that dendritic interactions between da neurons regulate the size and shape of dendritic fields. Ablation of a cluster of da neurons results in overgrowth of dendrites from adjacent hemisegments. The neurons within these clusters are morphologically diverse and only those sharing a similar morphology consistently innervate exclusive territories. These results suggested that dendritic interactions might show type selectivity. The present results from ablation and addition-of-neuron experiments suggest that repulsive dendritic interactions indeed occur between branches of like neurons to regulate dendritic field sizes, but they also indicate that neurons can show diverse responses to like dendrites. In particular, a fairly strict dendritic exclusion is observed among the class IV neurons, whereas dendrites of supernumerary class I, II, and III neurons overlap extensively with dendrites of resident same-class neurons. Thus, like-repels-like signaling may be a property only of neurons that provide a complete coverage of a receptive territory and, even among these neurons, may be restricted to specific regions of the dendritic arbor. How are dendritic fields defined among neurons that appear not to employ homotypic repulsion? Possibly, different types of neurons have different intrinsic growth capacitites determined by their expression of particular cell identity factors. Other growth-limiting factors might include genes that, when mutated, cause overgrowth phenotypes, such as flamingo, or as yet unidentified extrinsic limitations to dendrite extension (Grueber, 2003).
The da system of Drosophila shows notable similarities to and differences from other systems, such as the vertebrate retina and leech somatosensory system, in which tiling and interbranch repulsion have been studied. Destruction of small patches of retinal ganglion cells (RGCs) causes neighboring dendrites to grow preferentially toward the depleted area. Dendritic tiling by RGCs may generally involve interactions between dendrites of adjacent cells. This exclusion appears to occur independently of afferent inputs to RGC dendrites. Thus, even though da neuron dendrites are unlike RGC dendrites in that they have no known synaptic inputs, they may prove useful for identifying conserved mechanisms of dendrodendritic interaction. In the leech also, proper innervation of peripheral targets by pressure, touch, and nociceptive neurons requires both intra- and inter-neuronal interactions between sensory fibers. Anatomical and ablation studies in leech suggest that exclusion is most rigorous between different branches of the same neuron, less strict between homologous cells, and weak or absent if cells are of a different modality. The overlap of arbors of duplicated neurons, but not of branches belonging to the same neuron, may reflect such a hierarchy in the da system. The contrasting behaviors of isoneuronal and heteroneuronal branches of class I, II, and III neurons suggest that mechanisms of avoidance may differ for 'self' and 'non-self' branches. It is also possible that isoneuronal and heteroneuronal repulsion share some common molecular mechanism, but that physical continuity of arbors contributes to a more strict avoidance by isoneuronal branches (Grueber, 2003).
Several properties of the signals regulating tiling are implied in these results. (1) The interaction between dendrites seems to be inhibitory and can result in the turning of dendrites and/or the cessation of dendrite extension. (2) It is likely that the interaction is bidirectional. In other words, it is unlikely that one dendrite is only capable of sending out the signal while the other dendrite can only receive the signal. Lastly, because interactions occur between like dendrites and are required persistently, at least some molecules are likely to show a class-specific distribution in embryonic and larval stages. With the high resolution provided by the ppk-EGFP lines, it is feasible to carry out both candidate-based approaches and unbiased genetic screens to identify molecules involved in dendrodendritic interaction and tiling (Grueber, 2003).
The Drosophila external sensory organ forms in a lineage that is elaborated from a single precursor cell via a stereotypical series of asymmetric divisions. Hamlet transcription factor expression demarcates the lineage branch that generates two internal cell types, the external sensory neuron and thecogen. In Hamlet mutant organs, these internal cells are converted to external cells via an unprecedented cousin-cousin cell-fate respecification event. Conversely, ectopic Hamlet expression in the external cell branch leads to internal cell production. The fate-determining signals Notch and Pax2 act at multiple stages of lineage elaboration and Hamlet acts to modulate their activity in a branch-specific manner (Moore, 2004).
Tissues that develop from progenitor cells, including the vertebrate hematopoietic system and the central and peripheral nervous systems, generate multiple cell types from a single precursor via iterative cell divisions. The Drosophila external sensory organ (ESO) also forms in this way. It consists of five different cell types descended from one ESO precursor cell (ESOP) via a stereotypical series of asymmetric divisions (Moore, 2004).
ESOP cell division forms the IIA and IIB cells. The IIA gives rise to the external cells, the trichogen (hair), and the tormagen (the socket) that are visible on the surface of the cuticle (external cell [E]-branch). The IIB cell divides to give rise to neuronal and glial internal cell types that lie beneath the surface of the cuticle (internal cell [I]-branch). At each stage of elaboration, each cell can be clearly visualized and distinguished; hence, the ESO is an excellent model in which to examine the elaboration of multiple cell types from one precursor at the single-cell level in vivo (Moore, 2004).
Each division of the ESO lineage is asymmetric; one of the two cells formed inherits the Numb protein, causing it to have a lower level of Notch (N) activity than its sibling. N-mediated signaling between the siblings then determines a difference in identity between them. This difference is expressed in terms of gene expression (for example, the IIB cell expresses the transcription factor Prospero [Pros], whereas the IIA does not) and in terms of cell behavior (for example, the IIB cell divides with a different plane of mitotic spindle orientation to the IIA) (Moore, 2004).
The disruption of the function of genes that generate asymmetry between siblings (e.g., N) always leads to a sibling-sibling conversion. In many cases, the disruption of transcription factors required for cell differentiation also leads to sibling-sibling conversions; for example, loss of pros activity leads to IIB-to-IIA cell conversions at low frequency, and ectopic expression of Pros in the IIA cell converts this cell into a IIB. A second type of conversion is a nephew-uncle conversion; for example, in the Drosophila embryo, the Hamlet (HAM) transcription factor is required for external sensory (ES) neuron fate, and in the absence of Ham the ES neuron is converted to the IIIBsib cell. This represents a conversion between internal cell types, with a shared ancestor (IIB cell) that is a direct parent of one of the two cell types (Moore, 2004).
To date the only type of cell-fate conversions described in the ESOP lineage are sibling-sibling or nephew-uncle conversions. This is unsurprising given the binary nature of each cell-fate decision. Loss of HAM activity in the thecogen (and also the ES neuron in the adult ESO lineage) causes a fate switch not to that of an internal cell type, but to an external cell type. This switch represents a cousin-cousin conversion, which is shown to take place by a respecification mechanism. In ham mutants, the ES neuron and thecogen first express markers associated with the I-branch of the lineage, but they fail to fully differentiate and later convert into external cell types without first reentering the cell cycle. One role of Ham in the development of the ESO is to modulate the activity of N and Pax2 signals used at multiple points in the lineage in a branch-specific manner (Moore, 2004).
In the embryonic ESO lineage, Ham is expressed in the ES neuron but not in the multidendritic (MD) neuron. Loss of Ham function converts the ES to an (uncle) MD neuron fate, and indeed Ham acts as a binary genetic switch between these two internal cell fates. Ham is also expressed in the thecogen cell, which is the sibling of the ES neuron. If the thecogen cell undergoes a cell-fate conversion in the absence of Ham, however, it could not have switched fates to a sibling or uncle cell type, as both of these are neurons, and in ham mutant ES organs there is no increase in neuron number (Moore, 2004).
To investigate the fate of the 'thecogen' in a ham mutant, wild-type and ham mutant embryos were stained with antibodies to detect expression of the transcription factors Cut, Pros, and Pax2, and the placW enhancer trap A1-2-29. Cut marks all cells descended from the ESOP. Upon terminal differentiation of the ESO, Pax2 marks the thecogen and trichogen, Pros marks only the thecogen, and A1-2-29 drives ß-galactosidase expression in the trichogen and tormagen. In the dorsal external sensory (des) and ventral pore (vp) organs of ham mutant embryos, the total number of cells remains unchanged, and the thecogen cell (expressing Cut, Pax2, and Pros) is replaced by a cell expressing Cut, Pax2, and A1-2-29; this combination of markers normally defines trichogen fate. Given that this staining pattern implies that this cell is a trichogen, the ESO structures on the cuticle surface of ham mutant second instar larvae were examined. Sixty-five percent of organs showed a wild-type one-trichogen and one-tormagen phenotype, and 34% a two-trichogen and one-tormagen phenotype (Moore, 2004).
The replacement of the thecogen by a trichogen in the ham mutant could have occurred by two different mechanisms. In the first, an alteration of the ESO lineage division pattern is responsible for the replacement of an internal cell type by an external one. In the second, the thecogen derived from the IIIB cell is converted not to another cell type derived from the I-branch of the lineage, but to a cell type that is representative of the E-branch. These two possibilities have very different implications for understanding how the ESO develops. The first is consistent with the idea that all cell-fate decisions within this lineage are essentially binary and the fates of the daughters are restricted by the identity of the precursors giving rise to them. The second, in contrast, implies there is no such restriction (Moore, 2004).
In order to distinguish between these possibilities, the adult microcheate ESO lineage, in which the elaboration of each ESO derived from a single ESOP cell by live imaging, was analyzed. The adult ESO lineage is considered analogous to that of the embryo, except that the IIIBsib in the embryo becomes an MD neuron, whereas in the adult it undergoes apoptosis (Moore, 2004).
The Ham expression pattern in the adult ESO lineage is analogous to that seen in the embryo. Pupae were dissected at a stage in which the ESO lineage was elaborating and stained with antibodies to detect Ham, Pros, and the A101 enhancer trap. A101 is expressed in all cells of the ESO lineage and Pros is expressed, at least transiently, in all cells of the I-branch. Ham is first expressed in the IIIB cell and then inherited by its daughters, the ES neuron and thecogen (Moore, 2004).
Whether the supernumerary external cell seen in embryonic ham mutant ESOs was also present in the adult was investigated. The external phenotype of ham mutant ESO clusters was examined in nota mosaic for wild-type and ham mutant tissue. ham mutant ESOs were identified by the loss of Yellow (Y) in the thecogen and tormagen cells. Seven percent of y- sensory organs had a two-trichogen, one-tormagen phenotype similar to the ham mutant phenotype in the embryonic ESO. In addition, 42% of ham mutant ESOs had a one-trichogen, two-tormagen phenotype and 23% had a two-trichogen, two-tormagen phenotype (Moore, 2004).
To distinguish whether these supernumerary external cells have arisen from either an altered division pattern in the ESO lineage or conversion of terminal cell fates, live imaging of ESO lineage elaboration was carried in ham mutant clones between 18 and 38h after pupal formation (APF). ham mutant mosaic analysis via a repressible cell marker (MARCM). Clones were marked by Partner of Numb-GFP (PON-GFP) fusion protein expression; Pon is asymmetrically localized and inherited by only one daughter at each cell division of the ESO lineage. In ESO lineages in which the IIB cell has been converted to the IIA, for example, by ectopic expression of activated N in the IIB, the timing and orientation of the division of the cells of the I-branch are altered to resemble those of the E-branch. In contrast, the elaboration of ham mutant ESO lineages was indistinguishable from that in wild-type in the timing, orientation, and number of divisions in both the E-branch and the I-branch. Therefore, the supernumerary external cells in ham mutant clones are not due to a conversion of I-branch precursors into E-branch precursors or extra divisions within the E-branch itself; they are due to the conversion of the IIIB cell daughters to external cell fates (Moore, 2004).
The expression of I-branch specific markers was investigated in ham mutant ESO lineages during elaboration. ham mutant MARCM clones positively marked with mCD8GFP fusion protein expression were made in all ESOP-derived cells. ham mutant clones at all stages of ESO lineage elaboration were stained with antibodies that detected the following markers: Pros, Pax2, Elav (Embryonic lethal abnormal vision), which labels all differentiated neurons, and Suppressor of Hairless [Su(H)], which labels differentiated tormagen. In both wild-type and ham mutant lineages, the IIB, IIIB, and IIIBsib cells expressed Pros, thus confirming the live imaging findings that showed no differences between the elaborating I-branch in wild-type and ham mutant lineages (Moore, 2004).
The IIIB progeny in ham mutant clusters, however, shifted their patterns of differentiation over time. Shortly after division of the IIIB cell (22-24 h APF), one daughter in ham mutant clones continued to express Pros, similar to a wild-type thecogen, and the other began to express ELAV, a marker of neuron fate. By 28-30 h APF, the ham mutant ESO cell clearly differed from the wild-type control: expression of the I-branch-specific maker Pros was lost. Moreover, Elav-positive neurons were no longer present, but several ham mutant ESO showed small Elav-positive apoptotic cell fragments, indicative of the ES neuron undergoing cell death. Live confocal imaging of ham mutant clones showed the frequency of this event to be 15%. By 36-40 h, wild-type ESO clearly contained one trichogen and one thecogen (both Pax2-positive), one tormagen [Su(H)-positive], and one ES neuron (Elav-positive). In contrast, ham mutant ESOs contained no ES neurons or thecogen, two trichogen (Pax2-positive), and either one or two tormagen [Su(H)-positive]. Whereas mCD8GFP activity and Pax2 staining revealed the two-trichogen phenotype with 100% frequency, the appearance of two trichogens on the adult cuticle was less frequent, indicating that one supernumerary trichogen must have failed to grow out onto the cuticle surface. Costaining of ham mutant embryos with antibodies to detect Cut, Pros, and ELAV revealed that Pros is also transiently expressed in the thecogen cell before it undergoes conversion to a trichogen. Therefore, in both the adult and embryonic ham mutant ESO lineage, the daughters of the IIIB cell first express markers specific to internal cells, but expression of such markers ceases as these cells undergo respecification to an external cell fate (Moore, 2004).
In the ham mutant embryo, the ES neuron is transformed into a IIIBsib/MD neuron fate and the thecogen into a trichogen. On the basis of these embryo data, it is proposed that in the ham mutant adult, the thecogen is also converted into a trichogen and the ES neuron into either a IIIBsib (apoptotic cell) or a tormagen. A possible reason that the conversion properties of the ES neuron in the embryo are different from those of the adult could be that, as neuron-specific markers are already expressed in the ES neuron before it undergoes fate conversion, in the embryo, where a neuron-to-neuron respecification event can occur, it is favored over a neuron-to-nonneuron one (Moore, 2004).
If the cell-fate conversions that are proposed take place, then it would mean that the thecogen (high N) becomes a trichogen (low N) and the ES neuron (low N) can become a tormagen (high N). To confirm this, whether the high-N or low-N IIIB daughter cell becomes the supernumerary trichogen was investigated in a ham mutant ESO. ham MARCM clones were made in an Nts (temperature sensitive) background and N was inactivated in these clones at the stage where N-mediated signaling is generating asymmetry between the IIIB daughter cells. The resulting nota were stained with antibodies to detect mCD8, Su(H), and Pax2 and the fate of the IIIB daughter cells was examined. In the ham1, Nts ESOs 28/28 had a one-trichogen/multiple-tormagen phenotype, whereas in the ham1, N+ control 37/37 ESOs had a two-trichogen/multiple-tormagen phenotype (Moore, 2004).
This experiment clearly demonstrates that it is the high-N IIIB cell daughter that becomes the supernumerary trichogen, since reducing N activity results in a reduction in the number of trichogen to one in the ham mutant organ. The conclusion to be drawn from this experiment is, therefore, that whereas N is acting to determine the difference between daughters of an asymmetric division, of either IIA or IIIB, a second signal is acting that makes the trichogen similar to the thecogen and the tormagen similar to the ES neuron (Moore, 2004).
This study shows that in both the embryo and adult, ESO Ham is expressed solely in the IIIB cell and its daughters, the ES neuron and thecogen. Loss of Ham causes the conversion of the internal-cell-branch thecogen into an external-cell-branch trichogen by cell-fate respecification. In addition, loss of Ham in the ES neuron leads either to its conversion to an internal-cell-branch IIIBsib cell or an external-cell-branch tormagen. Therefore, Ham appears to act to determine the fate of the IIIB daughters with respect to all other terminally differentiated cell types in the ESO lineage. In other words, it acts as an intrinsic transcription factor determinant of IIIB cell-derived identity (Moore, 2004).
It was of interest to test whether Ham expression alone determines the difference between IIIB-derived and non-IIIB-derived fate. Ectopic expression of Ham in the embryonic IIB and IIIBsib cell (MD neuron) converts the IIIBsib into an ES neuron. This analysis was extended to the E-branch by using gal4109-68 to drive UAS-ham and UAS-mCD8GFP in all cells of the adult lineage. Ham expression in all ESO lineage cells led to the loss of both the E-branch-derived trichogen and tormagen from the surface of the cuticle. Antibody staining of the ESOs showed that I-branch-specific cell types had replaced these external cells. When Ham was ectopically expressed in the entire ESO lineage, five or six cells were seen, all of which were expressing Pros or Elav or (rarely) both Pros and Elav. In contrast, in a wild-type cluster, there are four cells including only one thecogen (Pros-positive) and one ES neuron (Elav-positive). These ectopic expression experiments confirm that Ham determines IIIB-derived versus non-IIIB-derived fate (Moore, 2004).
These ectopic expression experiments confirm that Ham determines IIIB-derived versus non-IIIB-derived fate. However, why in ham mutant ESOs are the transformations that occur thecogen (high N) to tricogen (low N) and ES neuron (low N) to tormagen (high N)? Pax2 expression in the ESO highlights a connection between these pairs of cell types; the thecogen and trichogen both express Pax2, whereas the tormagen and ES neuron do not. Moreover, Pax2 itself is required for hair-shaft differentiation in the trichogen, and ectopic Pax2 expression in the tormagen leads to ectopic hair-shaft development. In the thecogen, where Pax2 and Ham are coexpressed, Pax2 expression does not lead to hair-shaft development; however, in the absence of Ham, this cell now takes on a trichogen fate including the development of a hair shaft. Therefore one role of Ham in the thecgoen cell may be to suppress the ability of Pax2 to promote hair-shaft formation (Moore, 2004).
To investigate whether Ham can repress the hair-shaft-promoting activity of Pax2, Ham or Pax2 were expressed or Ham and Pax2 were coexpressed at high levels in all cells of the ESO lineage. neu-gal4 was used to drive expression of UAS-ham and/or UAS-Pax2; however, this causes embryonic lethality. To get around this problem, ectopic gene expression was driven only in notum clones. Ectopic expression of Pax2 led to organs with multiple hair shafts, some organs with misshapen external cells, and in some cases loss of external cells. In contrast, ectopic Ham or Ham and Pax2 caused the loss of external cells in almost 100% of ESO clones and never the formation of multiple hair shafts. These experiments demonstrate that Ham has the ability to modulate a Pax2-driven differentiation program, in this case, hair-shaft growth. Therefore, loss of Ham from the "thecogen" could lead to the depression of a program at least in part controlled by Pax2, which drives this cell to a trichogen fate (Moore, 2004).
The Pax2 cell-fate-determining signal is used at multiple points during the development of the ESO lineage, as is N. The presence or absence of Ham provides a branch-specific background state against which differentiating cells of the organ can interpret these signals. It is likely that a similar modulation of iterated signals by branch-specific factors occurs in vertebrate systems. For example, N signaling occurs at multiple points during the development of the hematopoietic lineage and could be modulated by the presence of branch-specific transcription factors. It is suggested that the analysis of Ham function in ESO lineage elaboration presented in this study provides useful insight into how cell fate is determined in many invertebrate and vertebrate lineages in which a single stem/precursor cell gives rise to multiple cell types via iterative cell divisions (Moore, 2004).
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date revised: 10 June 2004
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