Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous kidney disease that is the second most frequent cause of kidney failure in the first 2 decades of life. Despite the ...identification of mutations in more than 39 genes as causing SRNS, and the localization of its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain poorly understood and no universally safe and effective therapy exists to treat patients with this condition. Recently, genetic research has identified a subgroup of SRNS patients whose kidney pathology is caused by primary coenzyme Q10 (CoQ10) deficiency due to recessive mutations in genes that encode proteins in the CoQ10 biosynthesis pathway. Clinical and preclinical studies show that primary CoQ10 deficiency may be responsive to treatment with CoQ10 supplements bypassing the biosynthesis defects. Coenzyme Q10 is an essential component of the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. Studies in yeast and mammalian model systems have recently identified the molecular functions of the individual CoQ10 biosynthesis complex proteins, validated these findings, and provided an impetus for developing therapeutic compounds to replenish CoQ10 levels in the tissues/organs and thus prevent the destruction of tissues due to mitochondrial OXPHOS deficiencies. In this review, we will summarize the clinical findings of the kidney pathophysiology of primary CoQ10 deficiencies and discuss recent advances in the development of therapies to counter CoQ10 deficiency in tissues.
Karyomegalic interstitial nephritis (KIN) is a chronic interstitial nephropathy characterized by tubulointerstitial nephritis and formation of enlarged nuclei in the kidneys and other tissues. We ...recently reported that recessive mutations in the gene encoding FANCD2/FANCI-associated nuclease 1 (FAN1) cause KIN in humans. FAN1 is a major component of the Fanconi anemia-related pathway of DNA damage response (DDR) signaling. To study the pathogenesis of KIN, we generated a Fan1 knockout mouse model, with abrogation of Fan1 expression confirmed by quantitative RT-PCR. Challenging Fan1
and wild-type mice with 20 mg/kg cisplatin caused AKI in both genotypes. In contrast, chronic injection of cisplatin at 2 mg/kg induced KIN that led to renal failure within 5 weeks in Fan1
mice but not in wild-type mice. Cell culture studies showed decreased survival and reduced colony formation of Fan1
mouse embryonic fibroblasts and bone marrow mesenchymal stem cells compared with wild-type counterparts in response to treatment with genotoxic agents, suggesting that FAN1 mutations cause chemosensitivity and bone marrow failure. Our data show that Fan1 is involved in the physiologic response of kidney tubular cells to DNA damage, which contributes to the pathogenesis of CKD. Moreover, Fan1
mice provide a new model with which to study the pathomechanisms of CKD.
MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/− mice are healthier and longer-lived than ...control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. “MycKO” mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.
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•Postnatal body-wide deletion of the Myc gene in mice causes premature aging•“MycKO” mice dysregulate numerous genes involved in aging, senescence, and cancer•MycKO mice live longer and have a low lifetime cancer incidence•Normal aging in mice and humans is associated with Myc downregulation
Wang et al. show that the postnatal elimination of Myc causes premature aging and the deterioration of age-sensitive functions. Yet, these mice have extended lifespans and a reduced cancer incidence. Gradual Myc downregulation accompanies normal aging in many tissues. Thus, the strong relationship between aging and cancer can be severed by eliminating a single gene.
The sinus node (or sinoatrial node SAN), the pacemaker of the heart, is a functionally and structurally heterogeneous tissue, which consists of a large “head” within the right caval vein myocardium ...and a “tail” along the terminal crest. Here, we investigated its cellular origin and mechanism of formation. Using genetic lineage analysis and explant assays, we identified T-box transcription factor Tbx18-expressing mesenchymal progenitors in the inflow tract region that differentiate into pacemaker myocardium to form the SAN. We found that the head and tail represent separate regulatory domains expressing distinctive gene programs. Tbx18 is required to establish the large head structure, as seen by the existence of a very small but still functional tail piece in Tbx18-deficient fetuses. In contrast, Tbx3-deficient embryos formed a morphologically normal SAN, which, however, aberrantly expressed Cx40 and other atrial genes, demonstrating that Tbx3 controls differentiation of SAN head and tail cardiomyocytes but also demonstrating that Tbx3 is not required for the formation of the SAN structure. Our data establish a functional order for Tbx18 and Tbx3 in SAN formation, in which Tbx18 controls the formation of the SAN head from mesenchymal precursors, on which Tbx3 subsequently imposes the pacemaker gene program.
The mammalian urogenital system derives from multipotent progenitor cells of different germinal tissues. The contribution of individual sub-populations to specific components of the mature system, ...and the spatiotemporal restriction of the respective lineages have remained poorly characterized. Here, we use comparative expression analysis to delineate sub-regions within the developing urogenital system that express the T-box transcription factor gene Tbx18. We show that Tbx18 is transiently expressed in the epithelial lining and the subjacent mesenchyme of the urogenital ridge. At the onset of metanephric development Tbx18 expression occurs in a band of mesenchyme in between the metanephros and the Wolffian duct but is subsequently restricted to the mesenchyme surrounding the distal ureter stalk. Genetic lineage tracing reveals that former Tbx18+ cells of the urogenital ridge and the metanephric field contribute substantially to the adrenal glands and gonads, to the kidney stroma, the ureteric and the bladder mesenchyme. Loss of Tbx18 does not affect differentiation of the adrenal gland, the gonad, the bladder and the kidney. However, ureter differentiation is severely disturbed as the mesenchymal lineage adopts a stromal rather than a ureteric smooth muscle fate. DiI labeling and tissue recombination experiments show that the restriction of Tbx18 expression to the prospective ureteric mesenchyme does not reflect an active condensation process but is due to a specific loss of Tbx18 expression in the mesenchyme out of range of signals from the ureteric epithelium. These cells either contribute to the renal stroma or undergo apoptosis aiding in severing the ureter from its surrounding tissues. We show that Tbx18-deficient cells do not respond to epithelial signals suggesting that Tbx18 is required to prepattern the ureteric mesenchyme. Our study provides new insights into the molecular diversity of urogenital progenitor cells and helps to understand the specification of the ureteric mesenchymal sub-lineage.
•Descendants of Tbx18+ cells in the urogenital ridge contribute to the adrenals and gonads.•Descendants of Tbx18+ cells in the metanephric field contribute to the ureter and bladder mesenchyme and to the renal stroma.•Tbx18 is required in the ureteric mesenchyme to suppress renal stromal fates.•Tbx18 renders mesenchymal cells competent to respond to epithelial WNT and SHH signals.•Tbx18 expression in the ureteric mesenchyme is maintained by epithelial signals.
Acquisition and maintenance of vascular smooth muscle fate are essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of ...vascular smooth muscle cells (vSMCs) can result in structural alterations associated with aneurysms and vascular wall calcification. Here we report that maturation of sclerotome-derived vSMCs depends on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time, Notch/Jag1-mediated repression of sclerotome transcription factors Pax1, Scx, and Sox9 is necessary to fully enable vSMC maturation. Specifically, Notch signaling in vSMCs antagonizes sclerotome and cartilage transcription factors and promotes upregulation of contractile genes. In the absence of the Notch ligand Jag1, vSMCs acquire a chondrocytic transcriptional repertoire that can lead to ossification. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming, and promote vascular wall integrity.
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•Nuclear translocation of Notch at E14.5 coincides with a fate switch in the aorta•Notch/Jag1 in vSMC represses Sox9 and ectopic chondrogenesis•Constant Notch/Jag1 pressure maintains vSMC contractile gene and cell identity
Failure to acquire and maintain vascular smooth muscle cell (vSMC) fate leads to severe vascular disorders such as aneurysms and calcification. Briot et al. demonstrate that the Notch ligand Jag1 is required to prevent dedifferentiation and reprogramming of sclerotome-derived vSMC toward the chondrocytic lineage.
Osteoclast stimulation factor 1 (OSTF1) is an SH3-domain containing protein that was initially identified as a factor involved in the indirect activation of osteoclasts. It has been linked to spinal ...muscular atrophy in humans through its interaction with SMN1, and is one of six genes deleted in a human developmental microdeletion syndrome. To investigate the function of OSTF1, we generated an
Ostf1
knockout mouse model, with exons 3 and 4 of
Ostf1
replaced by a LacZ orf. Extensive X-Gal staining was performed to examine the developmental and adult expression pattern, followed by phenotyping. We show widespread expression of the gene in the vasculature of most organs and in a number of cell types in adult and embryonic mouse tissues. Furthermore, whilst SHIRPA testing revealed no behavioural defects, we demonstrate increased trabecular mass in the long bones, confirming a role for OSTF1 in bone development.
Nephronophthisis-related ciliopathies (NPHP-RCs) are developmental and degenerative kidney diseases that are frequently associated with extrarenal pathologies such as retinal degeneration, obesity, ...and intellectual disability. We recently identified mutations in a gene encoding the centrosomal protein SDCCAG8 as causing NPHP type 10 in humans. To study the role of Sdccag8 in disease pathogenesis, we generated a Sdccag8 gene-trap mouse line. Homozygous Sdccag8(gt/gt) mice lacked the wild-type Sdccag8 transcript and protein, and recapitulated the human phenotypes of NPHP and retinal degeneration. These mice exhibited early onset retinal degeneration that was associated with rhodopsin mislocalization in the photoreceptors and reduced cone cell numbers, and led to progressive loss of vision. By contrast, renal histologic changes occurred later, and no global ciliary defects were observed in the kidneys. Instead, renal pathology was associated with elevated levels of DNA damage response signaling activity. Cell culture studies confirmed the aberrant activation of DNA damage response in Sdccag8(gt/gt)-derived cells, characterized by elevated levels of γH2AX and phosphorylated ATM and cell cycle profile abnormalities. Our analysis of Sdccag8(gt/gt) mice indicates that the pleiotropic phenotypes in these mice may arise through multiple tissue-specific disease mechanisms.
Myc, a member of the "Myc Network" of bHLH-ZIP transcription factors, supervises proliferation, metabolism, and translation. It also engages in crosstalk with the related "Mlx Network" to co-regulate ...overlapping genes and functions. We investigated the consequences of stepwise conditional inactivation of Myc and Mlx in primary and SV40 T-antigen-immortalized murine embryonic fibroblasts (MEFs).
-knockout (
KO) and
×
"double KO" (DKO)-but not
KO-primary MEFs showed rapid growth arrest and displayed features of accelerated aging and senescence. However, DKO MEFs soon resumed proliferating, indicating that durable growth arrest requires an intact Mlx network. All three KO MEF groups deregulated multiple genes and functions pertaining to aging, senescence, and DNA damage recognition/repair. Immortalized KO MEFs proliferated in Myc's absence while demonstrating variable degrees of widespread genomic instability and sensitivity to genotoxic agents. Finally, compared to primary
KO MEFs, DKO MEFs selectively downregulated numerous gene sets associated with the p53 and retinoblastoma (Rb) pathways and G
/M arrest. Thus, the reversal of primary
KO MEF growth arrest by either Mlx loss or SV40 T-antigen immortalization appears to involve inactivation of the p53 and/or Rb pathways.
The mesothelium, the lining of the coelomic cavities, and the urothelium, the inner lining of the urinary drainage system, are highly specialized epithelia that protect the underlying tissues from ...mechanical stress and seal them from the overlying fluid space. The development of these epithelia from simple precursors and the molecular characteristics of the mature tissues are poorly analyzed. Here, we show that uroplakin 3B (Upk3b), which encodes an integral membrane protein of the tetraspanin superfamily, is specifically expressed both in development as well as under homeostatic conditions in adult mice in the mesothelia of the body cavities, i.e., the epicardium and pericardium, the pleura and the peritoneum, and in the urothelium of the urinary tract. To analyze Upk3b function, we generated a creERT2 knock-in allele by homologous recombination in embryonic stem cells. We show that Upk3bcreERT2 represents a null allele despite the lack of creERT2 expression from the mutated locus. Morphological, histological and molecular analyses of Upk3b-deficient mice did not detect changes in differentiation or integrity of the urothelium and the mesothelia that cover internal organs. Upk3b is coexpressed with the closely related Upk3a gene in the urothelium but not in the mesothelium, leaving the possibility of a functional redundancy between the two genes in the urothelium only.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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