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Klf6 Is a Zinc Finger Protein Expressed in a Cell-Specific Manner During Kidney Development

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Klf6 Is a Zinc Finger Protein Expressed in a Cell-Specific Manner During Kidney Development J Am Soc Nephrol 12: 726–735, 2001 Klf6 Is a Zinc Finger Protein Expressed in a Cell-Specific Manner during Kidney Development EVELYNE A. FISCHER,* MARIE-CHRISTINE VERPONT,* LEE ANN GARRETT-SINHA,† PIERRE M. RONCO,* and JEROME A. ROSSERT* *INSERM U 489 and University of Paris VI, AP-HP, Paris, France; and †The University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Abstract. Molecular mechanisms that are responsible for the expressed in the Wolffian duct but not in the mesonephric development of the renal collecting duct system during embry- mesenchyme. Thereafter, Klf6 was expressed in the ureteric ogenesis are still poorly understood. A mouse cDNA encoding bud and its branches and in the collecting ducts, whereas it was a zinc finger protein, called Klf6, which is a member of the not expressed in tubular structures that derive from the meta- Kru¨ppel-like family of transcription factors, has been cloned. nephric mesenchyme. Glomeruli were not labeled during early Northern blot analyses showed that Klf6 was already expressed stages of differentiation, and it is only at the capillary stage that in 11.5-d postconception mouse embryos and that its expres- a staining of the mesangial area was observed, which persisted sion persisted after birth. They also disclosed that Klf6 had a after birth. This pattern of expression is strikingly similar to the restricted pattern of expression. In situ hybridization experi- one of GATA-3, which is another zinc finger protein. It sug- ments using mouse embryos showed that during kidney devel- gests that Klf6 may play a role during kidney development and opment, Klf6 was expressed selectively in the Wolffian duct in particular during the development of the renal collecting and in its derivatives. During mesonephros development, it was duct system, possibly in association with GATA-3. In mammals, renal development proceeds in three stages (re- As for many other structures, the combinatorial action of viewed in reference 1). The first two stages lead to the forma- different cell-specific transcription factors is very likely to play tion of transient structures, the pronephros and the mesone- a critical role in the development of the Wolffian duct and of phros, and the third stage gives rise to the metanephros, which the ureteric bud. Different transcription factors such as Emx2, is the permanent kidney. During the development of the me- Pax-2, Lim-1, and GATA-2 are expressed in the ureteric bud sonephros, the Wolffian duct penetrates a nephrogenic mesen- and are involved in kidney development (reviewed in reference chyme and induces it to form nephric tubules. The formation of 2). Emx2 is expressed predominantly in the ureteric bud, and in the metanephros results from reciprocal inductive interactions mice that lack Emx2, the ureteric bud invades the metanephric between a mesenchymal structure, the metanephric blastema, mesenchyme but does not branch and never induces mesen- and an outgrowth of the Wolffian duct, the ureteric bud. The chymal cells to condense (3,4). Pax-2 is expressed both in the metanephric mesenchyme induces the ureteric bud to grow, ureteric bud and in the metanephric mesenchyme; mice that branch, and give rise to the collecting duct system. At the same lack Pax-2 do not have a ureteric bud, whereas hemizygous time, the ureteric bud induces the metanephric mesenchyme to mice have hypoplastic kidneys (5). Lim-1 is expressed in the condense around its tips and then to differentiate into epithelial ureteric bud and its derivatives and in the developing nephrons structures that ultimately will form the epithelial components (6). The very few Lim-1 null mice that survive until birth lack of the nephrons, through a multistep process. The condensed kidneys (7). GATA-2 is expressed in different tissues, includ- mesenchyme will successively differentiate into vesicles, com- ing the ureteric bud, and mice that do not express GATA-2 ma-shaped bodies, S-shaped bodies, and then nephrons. Paral- selectively in the developing kidney display an abnormal junc- lel to this differentiation process, the distal parts of the S- tion between the ureter and the bladder (8). A few other genes shaped bodies fuse with collecting ducts, and the proximal that encode transcription factors such as GATA-3 or Hoxb-7 parts of these structures become highly vascularized and form are also expressed in the developing ureteric bud (9,10), but glomeruli. their role in kidney development is still unknown. Zinc finger proteins have emerged as a major class of eukaryotic transcription factors. They are characterized by Received January 25, 2000. Accepted September 1, 2000. their DNA-binding domain containing cysteine or histidine Correspondence to Dr. Jerome A. Rossert, INSERM U489 and Department of residues that bind zinc atoms, and they can be divided into Nephrology, Tenon Hospital, 4 rue de la Chine, 75020 Paris, France. Phone: different subgroups depending on the amino acid residues that 33-1-56-01-60-29; Fax: 33-1-56-01-69-99; E-mail: [email protected] hop-paris.fr are important for zinc binding and on the spacing between 1046-6673/1204-0726 these amino acid residues. For example, factors that belong to Journal of the American Society of Nephrology the subfamily of Kru¨ppel-like transcription factors have two Copyright © 2001 by the American Society of Nephrology cysteine and two histidine residues that bind the zinc ion, and J Am Soc Nephrol 12: 726–735, 2001 Expression of Klf6 during Kidney Development 727 the consensus sequence of their zinc finger motif is Cys-X2Ϫ4- (Hybond-N, Amersham Pharmacia Biotech, Piscataway, NJ), and hybridized with a 32P-radiolabeled probe containing 192 bp of the Cys-X12-His-X3Ϫ4-His (reviewed in reference 11). This sub- family, which is itself part of the TFIIIA subclass (reviewed in coding sequence and 308 bp of the 3' untranslated region, following reference 12), includes ubiquitously expressed transcription standard procedures. After 18 to 20 h of hybridization, high-strin- factors but also transcription factors that have a restricted gency washes were performed, the last wash being done at 65°C for 10 min in 0.1 ϫ SSC (1 ϫ SSC is 0.15 M NaCl plus 0.015 M citrate pattern of expression and that can play important roles during Na), 0.1% SDS. To control for loading of RNA samples, each mem- organ differentiation, such as EKLF, LKLF, or GKLF/EZF brane was then stripped and reprobed using a 32P-radiolabeled probe (13–18). corresponding to the mouse glyceraldehyde-3-phosphate dehydroge- We report here the characterization of a mouse cDNA en- nase (GAPDH) gene. Labeling of the probes with [␣-32P]dCTP was coding a zinc finger protein, called Klf6, which belongs to the performed using a random priming labeling kit (Roche Diagnostics, Kru¨ppel-like family of transcription factors. Northern blot Basel, Switzerland) and following the manufacturer’s instructions. In analyses and in situ hybridization experiments showed that the some cases, the intensity of the signal was quantified using a Storm corresponding gene was expressed early during embryonic 860 PhosphorImager (Molecular Dynamics, Sunnyvale, CA). development and had a restricted pattern of expression. In particular, during kidney development, the expression of Klf6 In Situ Hybridization was restricted mostly to the collecting duct system, which The in situ hybridization study was performed using whole mouse suggests that this transcription factor may play a role during the embryos that ranged from 11.5 to 15.5 d p.c. and using different development of the renal excretory system. organs obtained from newborn mice and from 4-wk-old mice. Em- bryos and organs were collected under sterile conditions, fixed in Materials and Methods freshly made 4% paraformaldehyde at 4°C for 4 to 10 h, and embed- 35 Cloning of Klf6 ded in paraffin. Five to 7-␮ sections were made. S-radiolabeled Klf6 sense and antisense riboprobes were synthesized by in vitro transcrip- A partial cDNA encoding a protein called Klf6 was obtained using tion of a linearized pBluescript KS plasmid containing the 500-bp a method previously described for EZF (17). Briefly, poly(A)-RNA sequence that was used as a probe in Northern blot experiments. derived from 13.5-d postconception (p.c.) mouse embryos was used to Transcripts were synthesized using the maxiscript T3/T7 kit (Ambion, prepare first strand cDNA. These cDNA were then used as a template Austin, TX) and [35S]UTP, following the manufacturer’s instructions. in a PCR, with an oligo(dT) primer and two degenerate primers. These Before use, the RNA probes were incubated with1UofDNase I for primers (CACATCAGGACCCAC(C/T)ACIGG(A/G)GA and CA- 20 min at 37°C and purified using G50 columns (Amersham Phar- CATCCGIACCCA(T/C)ACIGG(T/C)GA) were homologous to an macia Biotech). Hybridization was performed as described by Sibony amino acid sequence that is conserved among several members of the et al. (19). Briefly, slides were deparaffinized, microwaved for 12 TFIIIA family of zinc finger proteins (HIRTHTGE). The PCR prod- min, refixed in 4% paraformaldehyde, digested with proteinase K (20 ucts were cloned into pBluescript KS (Stratagene, La Jolla, CA) and ␮g/ml), postfixed in 4% paraformaldehyde, dehydrated through in- hybridized with a second degenerate oligonucleotide (ACCGGC- creasing concentrations of ethanol, air dried, and incubated with the GA(A/G)AA(A/G)CCITT(T/C)G(A/C)TG) homologous to an over- probe (5 ϫ 104 to 5 ϫ 105 cpm/section) overnight at 50°C in a lapping region of the zinc finger domain (TGEKPFAC). cDNA from solution containing 2 ϫ SSC, 10% (wt/vol) dextran sulfate, 1 mg/ml 50 random positive clones were sequenced and compared with the denatured salmon sperm DNA (Roche Diagnostics), 70 mM DTT, and GeneBank database.
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