Functioning of an ABC transporter, Mdr49, in Hh signaling and germ cell migration

Deshpande, Girish; Manry, Diane; Jourjine, Nicholas; Mogila, Vladic; Mozes, Henny; Bialistoky, Tzofia; Gerlitz, Offer; Schedl, Paul

doi:10.1242/dev.133587

Cited by 11 publications

(7 citation statements)

References 55 publications

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“…In addition to the TargetScan database, a recent study provided a new set of binding sites for the top 59 CLIP-enriched miRNAs by assigning miRNA seed matches on PAR-CLIP and HITS-CLIP of Argonaute-1 (AGO1) ( Wessels et al, 2019 ). According to this study, miR-190 has 323 predicted targets ( Supplementary Table S3 ), of which seven genes are involved in Hh signaling, namely crooked neck ( crn ), Multi drug resistance 49 ( Mdr49 ), brother of odd with entrails limited ( bowl ), Cullin1 ( Cul1 ), Histone deacetylase 1 ( HDAC1 ), G protein-coupled receptor kinase 1 ( Gprk1 ), and Gprk2 ( Ou et al, 2002 ; Kent et al, 2006 ; Benítez et al, 2009 ; Cheng et al, 2010 ; Zhang et al, 2013a ; Liu et al, 2014 ; Deshpande et al, 2016 ). Among them, Crn, Mdr49, and Bowl are positive regulators of Hh signaling.…”

Section: Discussionmentioning

confidence: 99%

Dissection of the microRNA Network Regulating Hedgehog Signaling in Drosophila

Fan

Wang

et al. 2022

Front. Cell Dev. Biol.

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The evolutionarily conserved Hedgehog (Hh) signaling plays a critical role in embryogenesis and adult tissue homeostasis. Aberrant Hh signaling often leads to various forms of developmental anomalies and cancer. Since altered microRNA (miRNA) expression is associated with developmental defects and tumorigenesis, it is not surprising that several miRNAs have been found to regulate Hh signaling. However, these miRNAs are mainly identified through small-scale in vivo screening or in vitro assays. As miRNAs preferentially reduce target gene expression via the 3′ untranslated region, we analyzed the effect of reduced expression of core components of the Hh signaling cascade on downstream signaling activity, and generated a transgenic Drosophila toolbox of in vivo miRNA sensors for core components of Hh signaling, including hh, patched (ptc), smoothened (smo), costal 2 (cos2), fused (fu), Suppressor of fused (Su(fu)), and cubitus interruptus (ci). With these tools in hand, we performed a genome-wide in vivo miRNA overexpression screen in the developing Drosophila wing imaginal disc. Of the twelve miRNAs identified, seven were not previously reported in the in vivo Hh regulatory network. Moreover, these miRNAs may act as general regulators of Hh signaling, as their overexpression disrupts Hh signaling-mediated cyst stem cell maintenance during spermatogenesis. To identify direct targets of these newly discovered miRNAs, we used the miRNA sensor toolbox to show that miR-10 and miR-958 directly target fu and smo, respectively, while the other five miRNAs act through yet-to-be-identified targets other than the seven core components of Hh signaling described above. Importantly, through loss-of-function analysis, we found that endogenous miR-10 and miR-958 target fu and smo, respectively, whereas deletion of the other five miRNAs leads to altered expression of Hh signaling components, suggesting that these seven newly discovered miRNAs regulate Hh signaling in vivo. Given the powerful effects of these miRNAs on Hh signaling, we believe that identifying their bona fide targets of the other five miRNAs will help reveal important new players in the Hh regulatory network.

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Section: Discussionmentioning

confidence: 99%

Dissection of the microRNA Network Regulating Hedgehog Signaling in Drosophila

Fan

Wang

et al. 2022

Front. Cell Dev. Biol.

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“…Interestingly this notion is indeed supported by our recently published studies on an ABC transporter, mdr49, which has been implicated in PGC migration. 39 Ricardo and Lehmann screened embryos mutant in different ABC transporters for PGC migration defects. 40 Of the genes tested, mdr49 was the only transporter that had a significant effect on PGC migration.…”

Section: Localized Expression Of Hmgcr Is Necessary and Sufficient Fomentioning

confidence: 99%

“…Embryos were collected, fixed with paraformaldehyde and stained with anti-Vasa antibodies to examine the germ cell migration defects. Germ cell migration defects in stage 13-15 embryos were quantified to assess the extent of improvement(39). Panel A: mdr49 embryo (Stage 13) showing germ cell migration defects.…”

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confidence: 99%

Cells on the move: Modulation of guidance cues during germ cell migration

Deshpande

Barr

Gerlitz

et al. 2017

Fly

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In Drosophila melanogaster the progenitors of the germ-line stem cells, the primordial germ cells (PGCs) are formed on the outside surface of the early embryo, while the somatic gonadal precursor cells (SGPs) are specified during mid-embryogenesis. To form the primitive embryonic gonad, the PGCs travel from outside of the embryo, across the mid-gut and then migrate through the mesoderm to the SGPs. The migratory path of PGCs is dictated by a series of attractive and repulsive cues. Studies in our laboratory have shown that one of the key chemoattractants is the Hedgehog (Hh) ligand. Although, Hh is expressed in other cell types, the long-distance transmission of this ligand is specifically potentiated in the SGPs by the hmgcr isoprenoid biosynthetic pathway. The distant transmission of the Hh ligand is gated by restricting expression of hmgcr to the SGPs. This is particularly relevant in light of the recent findings that an ABC transporter, mdr49 also acts in a mesoderm specific manner to release the germ cell attractant. Our studies have demonstrated that mdr49 functions in hh signaling likely via its role in the transport of cholesterol. Given the importance of cholesterol in the processing and long distance transmission of the Hh ligand, this observation has opened up an exciting avenue concerning the possible role of components of the sterol transport machinery in PGC migration.

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“…Consequently, in Mdr49 mutant embryos, Hh is inappropriately sequestered in the hh-expressing cells. Supporting a role for Mdr49 in providing cholesterol for Hh modification, PGC migration defects in Mdr49 embryos are ameliorated by a cholesterol-rich diet (Deshpande et al, 2016).…”

Section: Introductionmentioning

confidence: 97%

Functional analysis of Niemann-Pick disease type C family protein, NPC1a, in Drosophila melanogaster

Bialistoky¹,

Manry

Smith

et al. 2019

Development

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During embryonic gonad coalescence, primordial germ cells (PGCs) follow a carefully choreographed migratory route circumscribed by guidance signals towards somatic gonadal precursor cells (SGPs). In Drosophila melanogaster, SGP-derived Hedgehog (Hh), which serves as a guidance cue for the PGCs, is potentiated by mesodermally restricted HMGCoA-reductase (Hmgcr) and the ABC transporter Multi-drug-resistant-49 (Mdr49). Given the importance of cholesterol modification in the processing and long-distance transmission of the Hh ligand, we have analyzed the involvement of the Niemann-Pick disease type C-1a (NPC1a) protein, a cholesterol transporter, in germ cell migration and Hedgehog signaling. We show that mesoderm-specific inactivation of Npc1a results in germ cell migration defects. Similar to Mdr49, PGC migration defects in the Npc1a embryos are ameliorated by a cholesterol-rich diet. Consistently, reduction in Npc1a weakens the ability of ectopic HMG Coenzyme A reductase (Hmgcr) to induce germ cell migration defects. Moreover, compromising Npc1a levels influences Hh signaling adversely during wing development, a process that relies upon long-range Hh signaling. Last, doubly heterozygous embryos (Mdr49/Npc1a) display enhanced germ cell migration defects when compared with single mutants (Npc1a/+ or Mdr49/+), supporting cooperative interaction between the two.

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Functioning of an ABC transporter, Mdr49, in Hh signaling and germ cell migration

Cited by 11 publications

References 55 publications

Dissection of the microRNA Network Regulating Hedgehog Signaling in Drosophila

Dissection of the microRNA Network Regulating Hedgehog Signaling in Drosophila

Cells on the move: Modulation of guidance cues during germ cell migration

Functional analysis of Niemann-Pick disease type C family protein, NPC1a, in Drosophila melanogaster

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