Neurl4 contributes to germ cell formation and integrity in<i>Drosophila</i>

Jones, Jennifer R.; Macdonald, Paul M.

doi:10.1242/bio.012351

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…This suggests that germ cell specification might be particularly sensitive to the activities of centrosome-associated proteins. Consistent with this, a role for Neurl4, a centrosome-associated protein, in germ cell specification and integrity has recently been revealed ( Jones and Macdonald, 2015 ).…”

Section: Introductionsupporting

confidence: 57%

Loss of function of theDrosophilaNinein-related centrosomal protein Bsg25D causes mitotic defects and impairs embryonic development

et al. 2016

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The centrosome-associated proteins Ninein (Nin) and Ninein-like protein (Nlp) play significant roles in microtubule stability, nucleation and anchoring at the centrosome in mammalian cells. Here, we investigate Blastoderm specific gene 25D (Bsg25D), which encodes the only Drosophila protein that is closely related to Nin and Nlp. In early embryos, we find that Bsg25D mRNA and Bsg25D protein are closely associated with centrosomes and astral microtubules. We show that sequences within the coding region and 3′UTR of Bsg25D mRNAs are important for proper localization of this transcript in oogenesis and embryogenesis. Ectopic expression of eGFP-Bsg25D from an unlocalized mRNA disrupts microtubule polarity in mid-oogenesis and compromises the distribution of the axis polarity determinant Gurken. Using total internal reflection fluorescence microscopy, we show that an N-terminal fragment of Bsg25D can bind microtubules in vitro and can move along them, predominantly toward minus-ends. While flies homozygous for a Bsg25D null mutation are viable and fertile, 70% of embryos lacking maternal and zygotic Bsg25D do not hatch and exhibit chromosome segregation defects, as well as detachment of centrosomes from mitotic spindles. We conclude that Bsg25D is a centrosomal protein that, while dispensable for viability, nevertheless helps ensure the integrity of mitotic divisions in Drosophila.

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Section: Introductionsupporting

confidence: 57%

Loss of function of theDrosophilaNinein-related centrosomal protein Bsg25D causes mitotic defects and impairs embryonic development

et al. 2016

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“…The three strongest interacting partners were SEC23IP, SRGAP2 and NEURL4 (Supplementary Fig. 5a ), which are linked to development 51 , 55 , 56 . These proteins are already reported to interact with HERC2 in human cell lines, validating our data 57 .…”

Section: Resultsmentioning

confidence: 99%

Insights into the ubiquitin-proteasome system of human embryonic stem cells

Sáez

Koyuncu

Gutiérrez-García

et al. 2018

Sci Rep

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Human embryonic stem cells (hESCs) exhibit high levels of proteasome activity, an intrinsic characteristic required for their self-renewal, pluripotency and differentiation. However, the mechanisms by which enhanced proteasome activity maintains hESC identity are only partially understood. Besides its essential role for the ability of hESCs to suppress misfolded protein aggregation, we hypothesize that enhanced proteasome activity could also be important to degrade endogenous regulatory factors. Since E3 ubiquitin ligases are responsible for substrate selection, we first define which E3 enzymes are increased in hESCs compared with their differentiated counterparts. Among them, we find HECT-domain E3 ligases such as HERC2 and UBE3A as well as several RING-domain E3s, including UBR7 and RNF181. Systematic characterization of their interactome suggests a link with hESC identity. Moreover, loss of distinct up-regulated E3s triggers significant changes at the transcriptome and proteome level of hESCs. However, these alterations do not dysregulate pluripotency markers and differentiation ability. On the contrary, global proteasome inhibition impairs diverse processes required for hESC identity, including protein synthesis, rRNA maturation, telomere maintenance and glycolytic metabolism. Thus, our data indicate that high proteasome activity is coupled with other determinant biological processes of hESC identity.

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“…Previous studies have shown that Neurl4 is required for initial steps of germplasm assembly during gametogenesis in Drosophila 15 . Neurl4 mutant embryos in Drosophila had reduced number of primordial germ cells as well as occurrence of primordial germ cells with abnormal morphology.…”

Section: Discussionmentioning

confidence: 97%

De novo mutations in idiopathic male infertility—A pilot study

et al. 2020

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Study question Are de novo mutations in the human genome associated with male infertility? Summary answer We identified de novo mutations in five candidate genes: SEMA5A, NEURL4, BRD2, CD1D, and CD63. What is known already Epidemiological and genetic studies have consistently indicated contribution of genetic factors to the etiology of male infertility, suggesting that more than 1500 genes are involved in spermatogenesis. Study design, size, duration First, we searched for de novo mutations in patients with idiopathic azoospermia with whole‐exome sequencing (WES). To evaluate the potential functional impact of de novo identified mutations, we analyzed their expression differences on independent testis samples with normal and impaired spermatogenesis. In the next step, we tested additional group of azoospermic patients for mutations in identified genes with de novo mutations. In addition to the analysis of de novo mutations in patients with idiopathic azoospermia, we considered other models of inheritance and searched for candidate genes harboring rare maternally inherited variants and biallelic autosomal and X‐chromosome hemizygous variants. Participants/materials, setting, methods We performed WES in 13 infertile males with idiopathic azoospermia and their parents. Potential functional impact of de novo identified mutations was evaluated by global gene expression profiling on 20 independent testis samples. To replicate the results, we performed WES in further 16 independent azoospermic males, which were screened for the variants in the same genes. Library preparation was performed with Nextera Coding Exome Capture Kit (Illumina), with subsequent sequencing on Illumina HiSeq 2500 platform. Main results and the role of chance We identified 11 de novo mutations in 10 genes of which 5 were considered potentially associated with azoospermia: SEMA5A, NEURL4, BRD2, CD1D, and CD63. All candidate genes showed significant differential expression in testis samples composed of patients with severely impaired and normal spermatogenesis. Additionally, we identified rare, potentially pathogenic mutations in the genes previously implicated in male infertility—a maternally inherited heterozygous frameshift variant in FKBPL gene and inframe deletion in UPF2 gene, homozygous frameshift variant in CLCA4 gene, and a heterozygous missense variant NR0B1 gene, which represent promising candidates for further clinical implication. Limitations of the study, reasons for caution We provided limited functional support for involvement of de novo identified genes in pathogenesis of male infertility, based on expression analysis. Additionally, the sample size was limited. Wider implications of the findings We provide support that de novo mutations might contribute to male infertility and propose five genes as potentially implicated in its pathogenesis.

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Neurl4 contributes to germ cell formation and integrity inDrosophila

Cited by 15 publications

References 40 publications

Loss of function of theDrosophilaNinein-related centrosomal protein Bsg25D causes mitotic defects and impairs embryonic development

Loss of function of theDrosophilaNinein-related centrosomal protein Bsg25D causes mitotic defects and impairs embryonic development

Insights into the ubiquitin-proteasome system of human embryonic stem cells

De novo mutations in idiopathic male infertility—A pilot study

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