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Regulated Vnd Expression Is Required for Both Neural and Glial Specification in Drosophila

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Regulated Vnd Expression Is Required for Both Neural and Glial Specification in Drosophila Regulated vnd Expression Is Required for Both Neural and Glial Specification in Drosophila Dervla M. Mellerick*, Victoria Modica Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan 48109 Received 5 July 2001; accepted 5 September 2001 ABSTRACT: The Drosophila embryonic CNS the ventral midline. The commissural vnd phenotype is arises from the neuroectoderm, which is divided along associated with defects in cells that arise from the me- the dorsal-ventral axis into two halves by specialized sectoderm, where the VUM neurons have pathfinding mesectodermal cells at the ventral midline. The neuro- defects, the MP1 neurons are mis-specified, and the ectoderm is in turn divided into three longitudinal midline glia are reduced in number. vnd over expression stripes—ventral, intermediate, and lateral. The ventral results in the mis-specification of progeny arising from nervous system defective, or vnd, homeobox gene is ex- all regions of the neuroectoderm, including the ventral pressed from cellularization throughout early neural neuroblasts that normally express the gene. The CNS of development in ventral neuroectodermal cells, neuro- embryos that over express vnd is highly disrupted, with blasts, and ganglion mother cells, and later in an unre- weak longitudinal connectives that are placed too far lated pattern in neurons. Here, in the context of the from the ventral midline and severely reduced commis- dorsal-ventral location of precursor cells, we reassess the sural formation. The commissural defects seen in vnd vnd loss- and gain-of-function CNS phenotypes using cell gain-of-function mutants correlate with midline glial de- specific markers. We find that over expression of vnd fects, whereas the mislocalization of interneurons coin- causes significantly more profound effects on CNS cell cides with longitudinal glial mis-specification. Thus, specification than vnd loss. The CNS defects seen in vnd Drosophila neural and glial specification requires that mutants are partly caused by loss of progeny of ventral vnd expression by tightly regulated. © 2002 John Wiley & neuroblasts—the commissures are fused and the longi- Sons, Inc. J Neurobiol 50: 118–136, 2002; DOI 10.1002/neu.10022 tudinal connectives are aberrantly positioned close to Keywords: NK-2; mutant; neurons; glia; axons INTRODUCTION roectodermal cells that are juxtaposed at either side of the ventral midline cells following gastrulation. A Central nervous system (CNS) specification is a subset of these neuroectodermal cells segregates to a highly intricate task accomplished by the sequential subepidermal location to form neuroblasts. Neuro- designation of progenitor cells and their progeny. In blasts are born in waves that are referred to as S1–S5. both invertebrates and vertebrates, conserved hierar- The timing of neuroblast birth and the positions neu- chical interactions of key regulators act to restrict the roblasts assume are relatively invariant (Campos-Or- potential of individual cells, or groups thereof, in a tega and Hartenstein, 1985; Doe, 1992). With each spatio-temporal context. In Drosophila, the embry- cell cycle the neuroblast buds off a ganglion mother onic CNS is generated from bilateral stripes of neu- cell (GMC), which divides once to generate a pair of sibling neurons (for review see Campos-Ortega, 1995). At the ventral midline, the mesectodermal cells * Present address: 8301 B, MSRB III, 1150 West Medical generate highly specialized neurons and glia (for re- Center Drive, Ann Arbor, MI 48109-0646. Correspondence to: D.M. Mellerick ([email protected]) view see Crews, 1998; Jacobs, 2000). Contract grant sponsor: NSF. Dorsal-ventral (D-V) and anterior-posterior (A-P) © 2002 John Wiley & Sons, Inc. pattern genes subdivide the neuroectoderm into lon- 118 vnd Expression and Neural and Glial Specification 119 gitudinal and horizontal stripes (for references and mediate neuroectodermal cells to that of their ventral review see Skeath, 1999; Cornell and Von Ohlen, analogues. In addition, there is a partial transforma- 2000). This causes the stereotypical regionalization of tion in the identity of lateral stem cells to that of their the early CNS, with neuroblasts positioned in three ventral counterparts. Disturbances in the normal vnd longitudinal columns along the D-V axis and in seven expression pattern result in the mis-specification of rows along the A-P axis. The restricted expression Even-skipped (Eve)-expressing GMCs and neurons domains of the three homeobox genes, ventral ner- (Chu et al., 1998; McDonald et al., 1998). The pat- vous system defective (vnd), intermediate neuroblasts terning changes observed in vnd loss- and gain-of- defective (ind), and muscle specific homeobox gene function mutants correlate with vnd’s capacity to re- (msh), in precise bilateral columns of neuroectoder- press ind and msh expression in ventral cells mal cells (Isshiki et al., 1997; Chu et al., 1998; Mc- (McDonald et al., 1998) and ind’s repression of msh Donald et al., 1998; Weiss et al., 1998) correspond to expression in intermediate cells (Weiss et al., 1998). the D-V columnar subdivision of the Drosophila neu- In this article we examine the effects of vnd mu- roectoderm. vnd is expressed in ventral neuroectoder- tation and over expression on CNS specification with mal cells (Jimenez et al., 1995; Mellerick and Niren- respect to cell identity. Neurons and glia were exam- berg, 1995), while ind expression is restricted to ined in the context of their origin from specific D-V intermediate neuroectodermal cells (Weiss et al., columns of precursor cells. We show that neurons that 1998), and msh is expressed in lateral neuroectoder- arise from ventral neuroblasts are obliterated in vnd mal cells (D’Alessio and Frasch, 1996; Isshiki et al., embryos. In addition, neurons that arise from the 1997). These D-V stripes of neuroectodermal cells in ventral midline are affected when vnd is missing in a turn give rise to the three columns of neuroblasts— non-cell autonomous manner. Moreover, RP2, which medial or ventral, intermediate, and lateral, respec- is derived from the intermediate neuroectoderm, is tively. Recent mutant analyses showed that vnd, ind, also nonautonomously affected. Ectopic vnd expres- and msh are critical for the specification of the ventral, sion results in a variety of effects, including the ab- intermediate, and lateral neuroblasts, respectively errant positioning of longitudinal connectives too far (McDonald et al., 1998; Chu et al., 1998; Weiss et al., from the ventral midline. The abnormal location of 1998; Buescher and Chia, 1997; Isshiki et al., 1997). the interneurons in vnd gain-of-function mutants is Separating the ventral neuroectodermal cells, the ven- related to the mis-specification of the longitudinal glia tral midline mesectodermal cells are specified by the that arise from the lateral neuroectoderm. The behav- transcription factor Single-minded (Sim). In some, but ior and/or presence of commissural neurons are also not all, respects the Drosophila CNS midline is func- affected by vnd over expression. A lower frequency of tionally equivalent to the floorplate of vertebrates (for midline crossing is observed when vnd is over ex- review and references see Crews, 1998; Jacobs, pressed, which correlates with the mis-specification of 2000). midline glia. Thus, ectopic expression of vnd causes The NK-2 type homeobox gene, vnd, is unique the mis-specification of neurons and glia that arise amongst previously described CNS-specific regula- from all D-V columns of neuroblasts. The implica- tory genes, because it is continuously expressed, from tions of these findings are discussed. cellularization until the completion of embryonic de- velopment, within the developing CNS. vnd is ex- pressed in ventral neuroectodermal cells and then in METHODS neuroblasts, as well as in GMCs, from the onset of cellularization until the completion of neuroblast del- Drosophila Strains, Heat Shock, and amination at stage 11. Later, the gene is widely ex- UAS-Gal4 Transgenic Lines pressed in neurons in a pattern relatively unrelated to the early expression pattern (Jimenez et al., 1995; The vnd 6 allele (Jimenez and Campos-Ortega, 1990) Mellerick and Nirenberg, 1995). vnd is essential both was used for loss-of-function analysis. The HS-vnd for the formation and identity of ventral neuroblasts. lines, where the pHSBJ-Casper vector (Jones and In vnd mutants the early S1 ventral MP2 and 7.1 McGinnis, 1993) was used to over express vnd, have neuroblasts are generally not formed (Skeath et al., previously been described (McDonald et al., 1998). 1994; Chu et al., 1998; McDonald et al., 1998), while vnd was ectopically expressed throughout the embryo the other surviving early ventral neuroblasts are mis- in the HS-vnd lines by collecting embryos from four specified, so they assume the identity of their inter- independent lines aftera1hlaying. Embryos were mediate counterparts. Conversely, over expression of then aged until they were 3 h old and then heat vnd leads to a transformation in the identity of inter- shocked on coverslips for 7 min at 36°Cin70% 120 Mellerick and Modica Figure 1 CNS defects in embryos that lack or over express vnd. The dissected CNS of BP102- stained embryos is shown; anterior is up. (A) In wild-type embryos BP102 stains the major axons of the CNS, including the bilateral longitudinal connectives, the anterior and posterior commissures, the VUM fascicle extending between the commissures, the ISN, and segmental nerves. (B) In vnd embryos the longitudinal fascicles are abnormally close, while the commissures are fused and irregular. The number of motor neurons is reduced. (C) In HS-vnd embryos the longitudinal connectives are reduced to clumps of neurons that are irregularly spaced and abnormally distant from the ventral midline. Some, but very few, fascicles cross the midline. (D) The CNS of progeny of UAS-vnd X Gal4-sca embryos. Although the longitudinal tracts are formed in “sca-vnd” embryos, they are discontinuous. In addition, the longitudinal connectives are located further from the midline than in wild-type embryos.
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