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Mutations in Lottchen Cause Cell Fate Transformations in Both Neuroblast and Glioblast Lineages in the Drosophila Embryonic Central Nervous System

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Mutations in Lottchen Cause Cell Fate Transformations in Both Neuroblast and Glioblast Lineages in the Drosophila Embryonic Central Nervous System Development 124, 673-681 (1997) 673 Printed in Great Britain © The Company of Biologists Limited 1997 DEV7540 Mutations in lottchen cause cell fate transformations in both neuroblast and glioblast lineages in the Drosophila embryonic central nervous system Marita Buescher and William Chia* Institute of Molecular and Cell Biology, National University of Singapore, Singapore 119260 *Author for correspondence (e-mail: [email protected]) SUMMARY The Drosophila embryonic central nervous system (CNS) distinct GMC4-2a-like cells that do not share the same develops from a stereotyped pattern of neuronal progeni- parental NB, indicating that a second NB has acquired the tor cells called neuroblasts (NB). Each NB has a unique potential to produce a GMC and a neuron which is identity that is defined by the time and position of its normally restricted to the NB4-2 lineage. Moreover, the ltt formation and a characteristic combination of genes it mutations lead to a loss of correctly specified longitudinal expresses. Each NB generates a specific lineage of neurons glia; this coincides with severely defective longitudinal con- and/or glia. Here we describe the genetic and phenotypic nectives. Therefore, lottchen plays a role in specifying the analysis of lottchen (ltt), a novel gene whose loss of function identity of both neuroblast and glioblast lineages in the causes a change in the identity of at least one NB as well as Drosophila embryonic CNS. We discuss the possibility that cell fate transformations within the lateral glioblast lineage. ltt may act to differentiate NB identity along the medial In wildtype embryos the parental NB of the motoneuron lateral axis. RP2 is NB4-2. ltt embryos are distinguished by an addi- tional RP2-like neuron which appears later in development. Key words: Drosophila embryonic CNS, neuroblast identity, We show that the two RP2 neurons are derived from two longitudinal glia, RP2 motoneuron INTRODUCTION differences between medial and lateral NBs are as yet unknown. NBs initiate unique cell lineages; each NB The central nervous system (CNS) is made up of two distinct undergoes several asymmetric cell divisions to generate, in a cell types: neurons and glia. Individual cells of both types show distinct temporal order, a set of unique intermediate precursor great diversity with respect to position, morphology and phys- cells called ganglion mother cells (GMCs); each GMC divides iological and biochemical properties. The relative simplicity of to produce two post-mitotic neuron/glia. These observations its embryonic CNS makes Drosophila a suitable model system (Doe, 1992) suggest that NB identity is dynamic and evolves for the study of developmental mechanisms that result in this in a unidirectional manner. Each GMC has a unique identity diversity. The neurons and glia of the Drosophila embryonic that is defined initially by the identity of the parental NB and CNS are arranged in a stereotypic pattern which is bilaterally ultimately by a specific combination of expressed genes. symmetric and segmentally reiterated. Each hemisegment It has been shown that individual neuroectodermal cells can contains ~300 neurons (Bossing et al., 1996b) and ~30 glia (Ito be labelled to reveal complete embryonic NB lineages et al., 1995) many of which can be identified according to their (Bossing and Technau, 1994). The terminal lineages of 17 NBs position and morphology. Furthermore, a large number of have been delineated (Udolph et al., 1993; Chu-LaGraff et al., genes have been described that are expressed in subsets of 1995; Bossing et al., 1996a,b): NB1-1 was found to generate neurons and glia and antibodies against these gene products the aCC/pCC neurons, several unidentified neurons and the A- provide molecular tools for the identification of specific cells. and B-glia. These findings indicate that neurons and glia are The neurons and glia are derived from ~30 progenitor cells not necessarily produced by distinct progenitors but that the called neuroblasts and glioblasts (NBs, GBs), respectively decision to adopt a neural or glial fate can occur within one (Goodman and Doe, 1993; Doe and Technau, 1993; Jimenez lineage (Udolph et al., 1993). This type of progenitor cell can and Modolell, 1993). NBs form in a characteristic manner and be described as neuro-glioblast. However, another group of each NB has a unique identity that is defined by the time of its glia, the longitudinal glia (LG) are derived from a progenitor birth and its position. NB identity is manifested in a specific cell whose ‘mode of division’ is different from that of NBs. At combination of expressed genes. Recent experiments have least six of the LG are derived from the lateral glioblast (LGB) shown that segment polarity genes play a role in the specifica- (Jacobs et al., 1989). The LG lineage has not yet been fully tion of NB identity along the anterior-posterior axis (for described. review: Doe and Skeath, 1996). In contrast, genes that specify To understand the developmental mechanisms that lead to 674 M. Buescher and W. Chia cell diversity within the CNS, it is important to define the TM3 male progeny (F1) was collected and crossed to DTS/TM3,Sb genetic and molecular components that act to specify cell fate. virgins. The F2 generation was raised at 28°C to eliminate progeny Previous studies have led to the identification of a large number that carry the dominant temperature-sensitve (DTS) lethal mutation. of genes and markers that are differentially expressed in The surviving flies, heterozygous for the EMS-treated chromosome and TM3,Sb were inbred to establish the final generation. Only lines subsets of NBs and GMCs (Broadus et al., 1995). However, + with several exceptions, their roles in cell fate determination with no Sb progeny, indicating the presence of a recessive lethal mutation, were screened by anti-Eve staining. are still poorly understood. From this point of view the best- studied lineage is that of NB4-2. The first-born GMC of NB4- Gamma-irradiation-induced mutagenesis 2, designated GMC4-2a (nomenclature according to Doe, Additional alleles of ltt were induced by irradiating st e iso3 males 1992) divides to produce the RP2 motoneuron and a sibling with 4500 rads from a Cobalt source. The mutagenised males were cell. Several genes have been described whose activities are mated en masse with w; TM6,Tb, e/TM3,Sb, e virgins. Single males required for the generation of a correctly specified RP2 neuron. of the F1 generation, heterozygous for the mutagenised chromosome The secreted gene product of wingless (Chu-LaGraff and Doe, and TM6,Tb, e, were crossed to virgin females of the genotype: lttEMS, 1993) is required for the formation and specification of NB4- e+/TM6, Tb, e. e males from vials that failed to yield Tb+ progeny (failed to complement lttEMS) were crossed to w; TM6,Tb, e/TM3,Sb, 2. In addition the homeobox genes fushi tarazu (ftz) and even- EMS skipped (eve) (Doe et al., 1988a,b) and the POU domain genes e virgins and balanced stocks were established. A ltt like phenotype was established by staining each line with anti-Eve, pdm1 and pdm2 are expressed in GMC4-2a and are necessary mAbBP102 and/or anti-Fasciclin II. for specifying its cellular identity and for the formation of the RP2 neuron (Yeo et al., 1995). The homeobox gene prospero Immunocytochemistry (pros; Doe et al., 1991; Vaessin et al., 1991) is expressed in Embryos were fixed and stained as previously described (Yang et al., many GMCs including GMC4-2a. Total loss of pros function 1993). For immunofluorescence FITC-conjugated anti-mouse affects the fate of many neurons including that of RP2. In antibody (Boehringer Mannheim) and biotinylated anti-rabbit addition, the putative transcription factor Huckebein appears to antibody in combination with avidin-Texas Red (Vector Laboratories) regulate aspects of GMC and neuronal identity required for the were used. ltt alleles were balanced over a ‘blue balancer’ chromo- correct differentiation of motoneurons arising from the NB4-2 some carrying an ubx-lacZ insertion to facilitate the identification of lineage (Chu-LaGraff et al., 1995). homozygous mutant embryos. The following antibodies were used: anti-Eve (rabbit, polyclonal; Despite this progress in understanding the specification of M. Frasch, The Mount Sinai Medical Center, N.Y.); anti-Eve the RP2 neuron, many components involved in this process (mouse, monoclonal; K. Zinn, Caltech), anti-Ftz (rabbit, polyclonal; are still unidentified. Here, we report the isolation of a set of W. Gehring, Biozentrum, Basel); mAbBP102, mAb22C10, anti-Fas- mutations in a novel gene, designated lottchen (name of twins ciclinII (mouse, monoclonal; C.S. Goodman, University of Califor- in the book ‘Das doppelte Lottchen’ by Erich Kaestner). In nia, Berkeley); anti-Pros (mouse, monoclonal, C.Q. Doe, University ltt loss-of-function mutant embryos the RP2 motoneuron of Illinois, anti-β-galactosidase (rabbit, polyclonal; ORGANON, appears to be duplicated and cell fate transformations are seen TEKNIKA CORPORATION). anti-Repo (RK2) (rabbit; G. in the LGB lineage. The extra RP2-like cell is not derived Technau, University of Mainz; rat; A. Tomlinson, Columbia Uni- from GMC4-2a, but from a GMC which appears later in versity). anti-Pdm1 (mouse and rabbit polyclonal, Yang et. al., development. This GMC expresses several molecular markers 1993). Anti-Zfh1 (mouse polyclonal; Z. Lai, University of Pennsyl- vania). indicative of a GMC4-2a identity, suggesting that the ltt mutations cause a duplication of GMC4-2a; however, the two Generation of β-gal-expressing ‘flipout’ clones GMCs don’t share the same parental NB, indicating that the To label individual NB lineages through the expression of TaulacZ ltt mutations cause a second NB to acquire the identity of we used the FRT/FLP system (Golic and Lindquist, 1989; Xu and NB4-2 (at least in part).
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