Lmx1a is required for the development of the ovarian stem cell niche in Drosophila

Abstract

The ovary serves as a model for pioneering studies of stem cell niches, with defined cell types and signaling pathways supporting both germline and somatic stem cells. The establishment of the niche units begins during larval stages with the formation of terminal filament-cap structures; however, the genetics underlying their development remains largely unknown. Here, we show that the transcription factor Lmx1a is required for ovary morphogenesis. We found that Lmx1a is expressed in early ovarian somatic lineages and becomes progressively restricted to terminal filaments and cap cells. We show that Lmx1a is required for the formation of terminal filaments, during the larval-pupal transition. Finally, our data demonstrate that Lmx1a functions genetically downstream of Bric-à-Brac, and is crucial for the expression of key components of several conserved pathways essential to ovarian stem cell niche development. Importantly, expression of chicken Lmx1b is sufficient to rescue the null Lmx1a phenotype, indicating functional conservation across the animal kingdom. These results significantly expand our understanding of the mechanisms controlling stem cell niche development in the fly ovary.

The Bric-à-Brac transcription factors are necessary for formation of functional germline stem cell niches through control ofdppexpression in theDrosophila melanogasterovary

“…Indeed, we found that when En/Inv were depleted in developing niches by RNAi, the same number of correctly formed TFs, TF cells and CCs were found as in controls. This is consistent with the observation of normal larval ovaries upon En/Inv depletion in Allbee et al (Allbee et al, 2018), using a different niche cell Gal4 driver and the same en/inv RNAi transgenes as used in our study. In contrast, another study, based on induction of clones of ovarian somatic cells homozygous for a null allele for both en/inv, concluded that these genes are involved specifically for proper TF cell alignment within individual stacks in larval ovaries (Bolívar et al, 2006).…”

“…In order to explore possible functional interactions between Bab and En/Inv proteins, we tested whether en/inv expression in niche cells of prepupal ovaries depends on Bab proteins. It has been reported that en/inv are specifically expressed in GSC niche cells as of the beginning of TF formation in the larval ovary (Allbee et al, 2018;Forbes et al, 1996;Green and Extavour, 2012;Mendes and Mirth, 2016). In addition, we found here a significant difference in En/Inv levels between TF cells and CCs in control prepupal niches (hs-FLP; FRT-bab AR07 /FRT-GFP and hhG>GFP, Fig 7A and 7A' and Fig 7B and 7B', green and yellow brackets, respectively), with a three-fold higher level in control TF cells than CCs (hs-FLP; GFP, Fig 7D).…”

“…A newly-identified gene necessary for ovary morphogenesis is Lmx1a, encoding a LIM-homeodomain transcription factor expressed in somatic apical cells, TF cells and CCs in the prepupal ovary (Allbee et al, 2018). Transcriptomic analysis revealed that en/inv are positively regulated by Lmx1a in ovaries at the larval to pupal transition, but Lmx1a was shown to be necessary for proper organization and differentiation of niche cells, unlike En/Inv.…”

Topology-driven protein-protein interaction network analysis detects genetic sub-networks regulating reproductive capacity

“…TF specification requires the expression of engrailed (En) ( Bolívar et al, 2006 ) and the transcription factors Bab1 and Bab2, encoded by the bric-à-brac locus ( Couderc et al, 2002 ; Godt et al, 1993 ). A third transcription factor, Lmx1a, was recently found to be necessary for the specification of the TFCs ( Allbee et al, 2018 ). Our hpo[RNAi] Ovariole Number sub-network identifies numerous additional novel transcription factors including bunched ( bun ) and retinoblastoma-family protein ( rbf ), which we hypothesise could also be involved in the specification of ovariole number.…”

Oncogenes in high grade serous adenocarcinoma of the ovary

“…Induced expression of LXM1B could rescue the signature of LMX1A loss-of-function. Thus both these genes could play a role in the development of ovary [ 70 ]. The role of LMX1B has not been thoroughly evaluated in any tumor type.…”