Deleting the mouse Hsd17b1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease

Jokela, Heli; Hakkarainen, Janne; Kätkänaho, Laura; Pakarinen, Pirjo; Ruohonen, Suvi T.; Tena‐Sempere, Manuel; Zhang, Fuping; Poutanen, Matti

doi:10.1038/s41598-017-16618-5

Cited by 12 publications

(11 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The impact of local changes in gene expression on the phenotypic spectrum of targeted mouse mutants has not been thoroughly studied. However, an accumulating number of reports indicate that some phenotypes associated with a targeted gene mutation are causally related to off-target effects on neighboring genes (17-21). For example, mice with a homozygous disruption of the Ampd1 gene generated by a targeted trap mutation (knockout-first allele) die within two days post-natally, and show reduced body weight, decreased lung saccular space and lack of milk in their stomach (20).…”

Section: Resultsmentioning

confidence: 99%

“…RNA-seq analysis revealed that expression of the neighboring Man1a2 and Nras genes was down-regulated in the knockout-first Ampd1 mice, but not in the conditional Ampd1 mutant mice. Another recent study reported that replacement of the coding region of the steroid metabolising enzyme gene Hsd17b1 with the lacZ gene inserted in the translation initiation site and a neo r selection cassette (Hsd17b1-LacZ/Neo mice) results in reduced adipose mass, increased lean mass and lipid accumulation in the liver of male mice (17). Further characterization revealed that the metabolic phenotype of Hsd17b1-LacZ/Neo mice is caused by the reduced expression of the immediate 5’ gene Naglu , which encodes the N-acetyl-alpha-glucosaminidase enzyme, and not by a deficiency in HSD17B1 activity.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Soulez¹,

Saba-El-Leil²,

Turgeon

et al. 2018

Preprint

View full text Add to dashboard Cite

38The physiological functions of the atypical MAP kinase ERK3 remain poorly characterized. 39Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus 40 (Mapk6 lacZ ) showed that inactivation of ERK3 in Mapk6 lacZ mice leads to perinatal lethality 41 associated with intrauterine growth restriction, defective lung maturation, and neuromuscular 42 anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel 43 mouse models expressing a catalytically-inactive (Mapk6 KD ) or conditional (Mapk6  ) allele of 44 ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive 45 the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant 46 mice reached adulthood, were fertile and showed no apparent health problem. However, analysis 47 56 57 Extracellular signal-regulated kinase 3 (ERK3) and ERK4 are atypical members of the mitogen-58 activated protein (MAP) kinase family (1). Despite their identification more than 25 years ago, 59 very little is known about their physiological functions. The ERK3 gene (MAPK6 in human) is 60 expressed ubiquitously in adult mammalian tissues, while ERK4 gene (MAPK4) shows a 61 restricted expression profile being detected mainly in brain tissue (2-4) 62 (www.gtexportal.org/home). During mouse embryogenesis, ERK3 mRNA and protein levels 63 peak around embryonic day 11, after the onset of organogenesis, and then decline thereafter (5). 64Expression of ERK3 is also up-regulated during in vitro differentiation of cell line models along 65 the neuronal or muscle lineage (2, 6). These early observations have suggested a potential role 66 for ERK3 signaling in cell differentiation and tissue development. 67 68 Analogous to classical MAP kinases, ERK3 is activated by phosphorylation of the activation 69 loop, which stimulates its intrinsic catalytic activity and affinity for the substrate MK5 (7). 70Activation loop phosphorylation is mediated by Group I p21-activated kinases (8, 9), and is 71 reversed by the action of the MAP kinase phosphatase DUSP2 (10). Of note, it has been 72 previously proposed that ERK3 enzymatic activity is dispensable for MK5 activation and that 73 ERK3 may exert a scaffolding function (11). However, other experiments using coupled in vitro 74 kinase assays did not suppport this hypothesis (7). A more recent study reported that 75 overexpression of ERK3 induces rounding of MDA-MB-231 breast cancer cells by an unknown 76 mechanism independent of its kinase activity (12). The physiological importance of catalytic and 77 non-catalytic functions of ERK3 remains an open question. 78 * Mixed C57Bl/6J-129/Sv genetic background

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Soulez¹,

Saba-El-Leil²,

Turgeon

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…The impact of local changes in gene expression on the phenotypic spectrum of targeted mouse mutants has not been thoroughly studied. However, an accumulating number of reports indicate that some phenotypes associated with a targeted gene mutation are causally related to off-target effects on neighboring genes (17)(18)(19)(20)(21). For example, mice with a homozygous disruption of the Ampd1 gene generated by a targeted trap mutation (knockout-first allele) die within 2 days postnatally and show reduced body weight, decreased lung saccular space, and lack of milk in their stomach (20).…”

Section: Erk3 Is Dispensable For Perinatal Survivalmentioning

confidence: 99%

“…RNA-seq analysis revealed that expression of the neighboring Man1a2 and Nras genes was downregulated in the knockout-first Ampd1 mice but not in the conditional Ampd1 mutant mice. Another recent study reported that replacement of the coding region of the steroid metabolizing enzyme gene Hsd17b1 with the lacZ gene inserted in the translation initiation site and a neo r selection cassette (Hsd17b1-LacZ/Neo mice) results in reduced adipose mass, increased lean mass, and lipid accumulation in the liver of male mice (17). Further characterization revealed that the metabolic phenotype of Hsd17b1-LacZ/Neo mice is caused by the reduced expression of the immediate 5= gene Naglu, which encodes the N-acetyl-␣-glucosaminidase enzyme, and not by a deficiency in HSD17B1 activity.…”

Section: Erk3 Is Dispensable For Perinatal Survivalmentioning

confidence: 99%

Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models

Soulez

Saba-El-Leil

Turgeon

et al. 2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6 lacZ ) showed that inactivation of ERK3 in Mapk6 lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6 KD ) or conditional (Mapk6 ⌬ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6 lacZ mice but not in Mapk6 KD or Mapk6 ⌬ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6 lacZ mutant mice.

show abstract

“…We have previously demonstrated that replacing the coding region of the HSD17B1 gene by a LacZ reporter results in marked down‐regulation in the expression of Naglu that is located upstream of the Hsd17b1 gene (29). To exclude the possibility that the male fertility phenotype in HSD17B1KO originates as a result of the down‐regulation of Naglu expression, we also analyzed male fertility and testis histology of NAGLUKO.…”

Section: Resultsmentioning

confidence: 99%

Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility

et al. 2018

Self Cite

View full text Add to dashboard Cite

The pituitary gonadotrophins and testosterone are the main hormonal regulators of spermatogenesis, but estradiol is also known to play a role in the process. The hormonal responses in the testis are partially mediated by somatic Sertoli cells that provide nutritional and physical support for differentiating male germ cells. Hydroxysteroid (17β) dehydrogenase 1 (HSD17B1) is a steroidogenic enzyme that especially catalyzes the conversion of low potent 17keto-steroids to highly potent 17β-hydroxysteroids. In this study, we show that Hsd17b1 is highly expressed in Sertoli cells of fetal and newborn mice, and HSD17B1 knockout males present with disrupted spermatogenesis with major defects, particularly in the head shape of elongating spermatids. The cell-cell junctions between Sertoli cells and germ cells were disrupted in the HSD17B1 knockout mice. This resulted in complications in the orientation of elongating spermatids in the seminiferous epithelium, reduced sperm production, and morphologically abnormal spermatozoa. We also showed that the Sertoli cell-expressed HSD17B1 participates in testicular steroid synthesis, evidenced by a compensatory up-regulation of HSD17B3 in Leydig cells. These results revealed a novel role for HSD17B1 in the control of spermatogenesis and male fertility, and that Sertoli cells significantly contribute to steroid synthesis in the testis.-Hakkarainen, J., Zhang, F.-P., Jokela, H., Mayerhofer, A., Behr, R., Cisneros-Montalvo, S., Nurmio, M., Toppari, J., Ohlsson, C., Kotaja, N., Sipilä, P., Poutanen, M. Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility.

show abstract

Deleting the mouse Hsd17b1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease

Cited by 12 publications

References 40 publications

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models

Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility

Contact Info

Product

Resources

About