Inactivation of Dicer1 in Steroidogenic factor 1-positive cells reveals tissue-specific requirement for Dicer1in adrenal, testis, and ovary
© Huang and Yao; licensee BioMed Central Ltd. 2010
Received: 20 November 2009
Accepted: 11 June 2010
Published: 11 June 2010
The synthesis of microRNA (miRNA) is a multi-step process that requires the action of the ribonuclease Dicer1. Dicer1 is responsible for the final processing of miRNA and has been implicated in cellular processes such as proliferation, apoptosis, and differentiation. Mouse embryos lacking Dicer1 die in early embryogenesis. In this study, we investigated whether Dicer1 is required for development of adrenal, testis, and ovary in mouse embryos.
To target Dicer1 deletion specifically in developing adrenals and gonads, we used Steroidogenic factor 1-cre (Sf1/Cre) line in which Cre recombinase is active in the progenitor cells of adrenals and gonads. Lack of Dicer1 in the SF1-positive cells did not affect formation and early differentiation of the adrenals and gonads. However, increasing numbers of apoptotic cells were first detected in the Dicer1 knockout adrenal cortex at 18.5 days post coitum (dpc), followed by apoptosis of somatic cells and germ cells in the testis at postnatal day 0. Affected adrenal and testes underwent complete degeneration 48 hrs after the onset of apoptosis. However, ovaries were not affected at least until postnatal day 5, when the animals died due to adrenal insufficiency.
Dicer1 is dispensable for formation and differentiation of fetal tissues derived from the SF1-positive adrenogonadal primordium. Dicer1 is essential for maintaining cell survival in adrenal and testis; however, development of the ovary from fetal stages to postnatal day 5 does not require the presence of Dicer1. Our results reveal a tissue-specific requirement of Dicer1 and microRNAs. Future research is needed to understand how the tissue-specific role of Dicer1 is established.
Dicer1 gene encodes a protein containing RNase III domains essential for miRNA biogenesis. miRNAs, which are 19-25 nucleotides long, non-coding RNAs, regulate gene expression by binding to target mRNAs in a sequence-specific manner, subsequently inhibiting their translation or inducing their degradation [1–3]. This post-transcriptional gene regulation machinery has been implicated in controlling diverse aspects of development in organisms from plants to mammals. In mice, general knockout (KO) of Dicer1 resulted in embryonic lethality around 7.5 dpc . Inability of Dicer1 KO embryonic stem cells to develop further highlights the role of miRNA machinery in maintaining stem cell population at early developing stages. Results from the tissue-specific KO of Dicer1 gene in mice have demonstrated the importance of miRNAs in organogenesis including heart, lung, limb and gonads [5–11].
Adrenal, testis, and ovary derive from a common primordium when they first arise in embryos. In the mouse embryo around 9.5 dpc, cells in the adrenogonadal primordium start to express the orphan nuclear receptor Sf1 [also known as Nr5a1, Ad4BP, or Ftzf1 (OMIM 184757)] . Between 10-11 dpc, the adrenogonadal primordium divides into adrenal primordium and gonadal primordium [13, 14]. The SF1-positive cells eventually differentiate into the cortical cells of the adrenal, Sertoli and Leydig cells of the testis, and granulosa and theca cells of the ovary.
The shared origin of SF1-positive cells in adrenal and gonads raise the possibility that a common regulatory mechanism is present for the establishment or maintenance of these cell lineages. Importance of Dicer1 and miRNAs has been documented in the adult testis and ovary [8–11]. In this study, we developed a mouse model in which Dicer1 gene was inactivated specifically in the SF1-positive cells in the adrenogonadal primordium, allowing us to study the overall functions of miRNAs in the development of adrenal, testis and ovary.
Ablation of Dicer1in SF1-positive cells causes prenatal degeneration of the adrenal cortex
To investigate the functions of Dicer1 in development of adrenals and gonads, we generated a conditional KO model in which Dicer1 alleles were inactivated specifically in the SF1-positive cells, the precursors for cortical cells in the adrenals and somatic cells in the gonads . The Dicer1-floxed allele has been shown to be a null allele upon Cre recombination in lung, limb, inner ear and germ cells [5, 6, 9, 16]. The Sf1/Cre mouse line expresses high levels of Cre recombinase in the adrenogonadal primordium at 10 dpc . We and others have used this Sf1/Cre line to remove or activate genes in the adrenogonadal primordium and observed adrenal and gonadal phenotypes at as early as 12.5 dpc [17–19].
Ablation of Dicer1in the SF1-positive cells causes testis degeneration after birth
Ablation of Dicer1does not disturb fetal and neonatal development of the ovary
In the Sf1/Cre-mediated Dicer1 KO mice, adrenal cortical cells are the first SF1-positive population that undergoes apoptosis at fetal stages, followed by testicular Leydig cells and Sertoli cells, respectively. Adrenal degeneration in the Dicer1 KO starts between 16.5-18.5 dpc and by the time of birth, adrenal cortical cells are almost completely abolished. In the testis, however, degeneration becomes apparent only after birth and progresses rapidly. Loss of somatic cells in the testes eventually leads to germ cells loss in the Dicer1 KO testis. By P5, almost all of the functional structures and cell types in the testis are no longer present. Intriguingly, ovaries, which derive from the same SF1-positive primordium as adrenal and testis, show no morphological and cellular changes from fetal stages to P5 in response to the loss of Dicer1. Increased apoptosis has been reported in tissues that lack Dicer1 [5–8]. Increased cell death in testes and adrenals in our study further suggests that Dicer1 and microRNAs processed by DICER play a universal role in maintaining cell survival.
In the adrenal, the cortical cells are derived from at least two sources: 1) the SF1-positive adrenal primordium, which forms the foundation of the organ and 2) SF1-negative capsular cells, which contribute to further growth of the adrenocortex [23–26]. It is known that loss of Sf1 leads to apoptosis of adrenal cortical cells and adrenal dysgenesis at birth [14, 27]. Loss of Dicer1 in the SF1-positive cortical cells also leads to apoptosis of the cortex; however, the degeneration process occurs much later than that in the case of Sf1 KO. It is possible that DICER-regulated miRNAs control genes that are critical for cortical cells survival, such as Sf1. However, in the Dicer1 KO adrenal, SF1 is still present in the remaining cortical cells. Depletion or mutation of Cited2, Wt1, and Pbx1 also resulted in prenatal adrenal dysgenesis in mouse embryos [28–30]. Involvement of Dicer and miRNAs in regulation of these genes in adrenal development remains to be determined.
Adrenocortical degeneration was also reported in β-catenin conditional KO mice . β-catenin deficiency mediated by the same Sf1/Cre resulted in underdeveloped adrenal cortex; however, no apoptosis was found at fetal stages. These data suggest that regulation of adrenal development via β-catenin is probably independent from DICER-regulated miRNA machinery or vice versa.
Dicer and other components of the miRNA-mediated interference machinery are present in the testis, including germ cells and Sertoli cells [31–34]. Germ cell-specific Dicer1 KO mice were generated using the TNAP/Cre that is active in the primordial germ cells [9, 10]. Loss of Dicer1 in germ cells led to defects in proliferation and differentiation of spermatogonia and abnormal morphology and motility of sperm [9, 10]. Sertoli cell-specific Dicer1 KO mice was generated using the anti-Müllerian hormone Cre (Amh-cre) line that targets Sertoli cells starting at ~15.5 dpc . Loss of Dicer1 in Sertoli cells resulted in impaired spermatogenic waves and complete absence of spermatozoa. In addition, increased Sertoli cell apoptosis was found at P5 and germ cells underwent apoptosis at P15, eventually leading to complete testis degeneration at P180. In our Sf1/Cre-mediated Dicer1 KO model, we targeted both Sertoli cells and Leydig cells at an earlier stage (10-11 dpc). We observed testicular degeneration at an earlier time point and in a more dramatic fashion than was reported in the Sertoli cell Dicer1 KO. In our model, almost all testicular structures and cell types were absent at P5. As expected, both Sertoli and Leydig cell populations underwent apoptosis albeit within different time frames (the number of Leydig cells decreases first, followed by Sertoli cells). Although male germ cells are negative for SF1, their survival was affected in the somatic cell-specific Dicer1 KO testis. This is expected as Sertoli cells are known to provide structural supports and differentiation cues to support spermatogenesis . Although Leydig cells were also affected in our model, we do not believe that their demise is responsible for the germ cell loss phenotypes based on the fact that male germ cells are not known to respond to androgens, the major product of Leydig cells.
Dicer1 is also expressed in the female reproductive tract and the ovary, including oocytes, theca cells and granulosa cells [36–39]. Many miRNAs are synthesized in ovaries at different stages of folliculogenesis [40–42]. It has been reported that morphogenesis and function of the female reproductive tract were affected in the absence of Dicer1 . To study the in vivo role of Dicer1 in the mouse ovary, granulosa cell specific Dicer1 KO mice were generated by using Amhr2/Cre, which is expressed in granulosa cells of preantral and antral follicles [11, 43–45]. Two different Dicer1-floxed strains were used and both showed that loss of Dicer1 in granulosa cells resulted in decreased ovulation rate, trapped oocytes in luteinized follicles and increased numbers of atretic follicles [11, 18, 46]. Fertilized oocytes collected from granulosa cell-specific Dicer1 KO females had decreased ability to progress to the two-cell stage . We were not able to examine the consequence of loss of Dicer1 on folliculogenesis due to death of Dicer1 KO animals after P5 as a result of adrenal cortex degeneration. However at least at P5, Dicer1 KO ovaries show no signs of degeneration.
Based on findings from our lab and others, Sf1/Cre-medicated gene deletion occurs in adrenals and gonads at 10-11 dpc. In the Sf1/Cre-mediated Dicer1 KO embryos, defects in adrenals and testes did not become apparent until 18.5 dpc and P0, respectively, and the ovaries were not affected. The extended delay between deletion of Dicer and the appearance of phenotypes suggests that Dicer and/or microRNAs have a substantial half-life . It also raises the possibilities that (i) these organs have different turn-over rate of Dicer and/or Dicer-induced microRNAs, (ii) these three organs have different thresholds of tolerance toward the loss of Dicer1 and microRNAs, and/or (iii) Dicer and microRNAs play tissue-specific roles among these three organs. In the Sertoli cell-specific Dicer1 KO testis, the significant alternations in gene expression have already occurred at the time when structural changes are not yet detectable. We are currently testing these three possibilities by performing a time course analysis of changes in Dicer1 mRNA, Dicer protein and microRNAs in these three tissues after Dicer1 ablation.
Generation of conditional Dicer1knockout mice
Conditional Dicer1 KO mice were generated by crossing Sf-1/Cre transgenic mice  with Dicer1 f/f mice (Dicer1 tm1Bdh , obtained from the Jackson Laboratory) [5, 6, 9, 16]. The genetic background of these mice was mixed C57BL/6J and SV129. Female and male mice were paired together and checked for the presence of a vaginal plug the next morning. The day when the vaginal plug was detected was considered 0.5 day post coitum or dpc. Samples were collected at 14.5 dpc, 16.5 dpc, 18.5 dpc, birth (P0), postnatal day 2 and 5 (P2 and P5). The genotype was determined by polymerase chain reaction (PCR) of tail DNA [6, 19]. All procedures described were reviewed and approved by the Institutional Animal Care and Use Committee at University of Illinois and were performed in accordance with the Guiding Principles for the Care and Use of Laboratory Animals. All experiments were performed on at least three animals for each genotype.
The specimens were fixed in 4% paraformaldehyde/phosphate-buffered saline (PBS) at 4°C overnight, and embedded in paraffin following standard procedures for sectioning. For immunofluorescence analysis, paraffin embedded sections were dewaxed and rehydrated in a series of alcohol/PBS gradient. The endogenous peroxidase activity was blocked by 3% H2O2 in methanol for 8 minutes and rinsed with PBS 3 times for 5 minutes each. Slides were pretreated in 0.1 mM citrate acid for 20 minutes in the microwave. After preincubating with 1.5% normal donkey serum in PBS for 30 minutes, sections were incubated with either anti-SF1, anti-CYP21 (1:1000, kindly provided by Dr. B-c Chung, Academia Sinica, Taiwan), anti-TH (1:1000, Millipore, Billerica, MA, USA), anti-3βHSD, anti-SOX9 (1:1000, kindly provided by Dr. K. Morohashi, National Institutes of Natural Sciences, Japan.), anti-Laminin (1:500, Sigma-Aldrich, St. Louis, MO, USA), anti-TRA98 (1: 1000 kindly provided by Dr. H. Tanaka, Osaka University, Japan), anti-cleaved Caspase-3 (1:500, Cell Signaling, Danvers, MA, USA) or anti-Ki67 antibody (1:1000, BD Biosciences, San Jose, CA, USA) in PBST containing 1.5% normal donkey serum at 4°C overnight. After rinsing with PBST, sections were incubated with secondary antibody for 30 minutes and processed for signal detection according to the manufacturer's protocol (TSA kit, PerkinElmer, Waltham, MA, USA). For double-fluorescent staining of anti-cleaved Caspase-3 with other antibodies, staining of cleaved Caspase-3 were performed first as described above, samples then were double stained for the other antibodies using different fluorescent-label secondary antibodies. For other double-fluorescent staining, tissue sections were treated with two different primary antibodies generated from different species, followed by appropriate secondary antibodies. At least three animals were examined for each genotype.
TUNEL assay was performed on 5 μm paraffin sections using Roche's TUNEL assay kit (Roche Co., Ltd., Indianapolis, IN, USA) according to the manufacturer's instructions.
List of Abbreviations
polymerase chain reaction
Phosphate Buffered Saline Tweeen-20
Steroidogenic factor 1
We would like to thank the following collaborators for providing the antibodies: Dr. Bon-chu Chung (SF1 and CYP21 antibodies), Dr. Ken Morohashi (SOX9 antibody), and Drs. Hiromitsu Tanaka and Yoshitake Nishimune (TRA98 antibody). We also appreciate all of the Yao lab members for their assistance and support. This study was funded by National Institute of Health (HD046861 and HD059961to H.H.Y) and the Billie Field Memorial Fellowship to C.J.H. We would like to dedicate this study to our collaborator and friend Dr. Keith Parker, who passed away on December 13, 2008.
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