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Expression of MUL, a gene encoding a novel RBCC family ring-finger protein, in human and mouse embryogenesis
Mechanisms of Development 108 (2001) 221–225 www.elsevier.com/locate/modo
Gene expression pattern
Expression of MUL, a gene encoding a novel RBCC family ring-finger protein, in human and mouse embryogenesis Anna-Elina Lehesjoki a, Victoria A. Reed b, R. Mark Gardiner c, Nicholas D.E. Greene b,* a
Folkha¨lsan Institute of Genetics and Department of Medical Genetics, Biomedicum Helsinki, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland b Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK c Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK Received 4 April 2001; received in revised form 12 July 2001; accepted 18 July 2001
Abstract We studied the expression of MUL, a gene encoding a novel member of the RING-B-Box-Coiled Coil family of zinc finger proteins that underlies the human inherited disorder, Mulibrey nanism. In early human and mouse embryogenesis MUL is expressed in dorsal root and trigeminal ganglia, liver and in epithelia of multiple tissues. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: MUL; Mulibrey nanism; Ring-finger; RING-B-Box-Coiled Coil protein; Zinc-finger; Wilms tumour; Mouse embryo; Human embryo; Dorsal root ganglia; Trigeminal ganglia; Epithelium; Inherited diseases; Growth retardation
1. Results and discussion Mutations of MUL underlie the autosomal recessive disorder, Mulibrey nanism (for muscle–liver–brain–eye nanism; Avela et al., 2000), which is characterised by prenatal-onset growth failure and pericardial constriction with subsequent hepatomegaly (Perheentupa et al., 1973; Lapunzina et al., 1995). Other features include typical dysmorphic features, J-shaped sella turcica, yellowish dots in the ocular fundi and hypoplasia of various endocrine glands. About 4% of Mulibrey nanism patients develop Wilms tumour (Simila¨ et al., 1980; Seemanova´ and Bartsch, 1999). Northern blot analysis of MUL indicated widespread expression in adult tissues (Avela et al., 2000). MUL encodes a predicted 108 kDa member of the RING-BBox-Coiled-Coil (RBCC) protein family. The RING-finger motif is found in many proteins and has been implicated in mediating protein interactions critical for transcriptional repression and ubiquitination (Borden, 2000). RING fingers may occur in association with other domains, such as the RBCC that characterises a subfamily of zinc finger proteins, the functions of which are largely unknown. Several members of this subfamily play a role in development * Corresponding author. Tel: 144-20-7905-2230; fax: 144-20-78314366. E-mail address: [email protected] (N.D.E. Greene).
including MID1, the gene for X-linked Opitz syndrome, MURF, which acts in skeletal myoblast differentiation in the mouse, and lin-41 in Caenorhabditis elegans (Quaderi et al., 1997; Spencer et al., 2000; Hong et al., 2000). We analysed MUL expression during mouse and human embryogenesis. In mouse, no MUL expression is detected at E8.5 and only very weak, generalised expression is detected at E9.5, E10.5 and E11.5 (data not shown). However, at E11.5 specific staining is also apparent in cells lining the oesophagus and bronchi (Fig. 1A) and in the innermost cells of the optic cup, adjacent to the lens (arrowhead in Fig. 1B). Between E12.5 and E14.5, MUL expression is widespread (Fig. 1). MUL is intensely expressed in the trigeminal and sympathetic ganglia (Fig. 1C,D) and dorsal root ganglia throughout the length of the body axis (Fig. 1D,K). Uniform intense expression is also detected in the liver (Fig. 1D). Among the remaining tissues, MUL expression is frequently localised in epithelia of ectodermal or endodermal origin but is absent from the neuroepithelium and mesothelium. Intense expression is seen in gut epithelium of the midgut (Fig. 1E,K), stomach (data not shown) and oesophagus (Fig. 1F). Expression is also detected in the olfactory epithelium (Fig. 1I), in the epithelial lining of the bronchioles (Fig. 1J), and in the surface ectoderm (Fig. 1D,I). In the developing eye, MUL is expressed in the lens epithelium and the neural layer of the retina but not in the optic nerve (Fig. 1G,H).
0925-4773/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0925-477 3(01)00491-9
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Fig. 1. Expression of MUL in mouse embryogenesis. In situ hybridisation on transverse (A–I,L) and sagittal (J,K,M) sections indicates that MUL is expressed in multiple tissues. At E11.5, expression is detected in oesophagus, bronchi and retina (A,B). At E14.5 (C–M) MUL is expressed in trigeminal (C), dorsal root (D) and sympathetic (arrow in D) ganglia and epithelial cells in several tissues including midgut (E), oesophagus (F), lens (G,H), nasal epithelium (I), bronchioles (J), kidney (K,L). Arrowheads: (B) optic cup cells (future inner layer of retina), (G) lens epithelium, (D,I) surface ectoderm. Arrows: (D) sympathetic ganglion, (E) midgut epithelium, (H) optic nerve, (L) mesonephric duct, (M) vibrissa primordia. Abbreviations: a, primordium of adrenal gland; b, bronchi; d, dorsal root ganglia; e, oesophagus; k, kidney; li, liver; m, mouth; o, olfactory epithelium; p, pancreas; r, retina; s, submandibular gland; t, thyroid; te, testis; to, tongue; tr, trigeminal ganglia; u, upper lip. Scale bar: 0.04 mm (D,F,I–M); 0.02 mm (A–C,E,G,H).
A.-E. Lehesjoki et al. / Mechanisms of Development 108 (2001) 221–225
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Fig. 2. Expression of MUL in a human embryo at 10 weeks post-fertilisation. In situ hybridisation on transverse sections (A–H). Intense expression is detected in dorsal root and trigeminal ganglia (A, B), liver (D) and submandibular gland (H) as well as epithelia of several tissues including lens (C), gut (D), bronchioles (E), kidney (F,G), pancreas (G). Arrowhead (C), lens epithelium; arrow (D), midgut epithelium. Abbreviations: d, dorsal root ganglia; k, kidney; li, liver; n, neural tube; p, pancreas; s, submandibular gland; tr, trigeminal ganglia. Scale bar: 0.04 mm (A,C–G); 0.02 mm (B,H).
In the kidney (Fig. 1K,L) MUL expression is detected in the epithelium of the developing nephron, in the commaand s-shaped bodies that are formed following mesenchymal–epithelial transformation of the mesenchyme that condenses around the ureteric bud. Thus, MUL appears to
co-localise, at least partially, with another Wilms tumour associated gene, WT1 (Armstrong, 1993; Pritchard-Jones, 1999). MUL is also expressed in the mesonephric duct (Fig. 1L). In the pancreas, expression is again detected in the epithelial component (Fig. 1E) that includes ductal cells
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that differentiate into mature endocrine and exocrine cells under the control of mesenchymal signals (Teitelman et al., 1993; Scharfmann, 2000). Expression is also evident in the placodes that are the primordia of the vibrissae (Fig. 1M), development of which also depends on epithelial–mesenchymal interactions (Hardy, 1992; Powell et al., 1998). Additional epithelial sites of expression are certain glands, notably the thyroid and submandibular glands (Fig. 1F) and the medulla (but not cortex) of the adrenal glands (Fig. 1K). Intense expression is detected in the primitive seminiferous tubules of the developing testis at E14.5 (Fig. 1L). The expression of MUL in human embryos was examined at 4, 7 and 10 weeks post-fertilisation, equivalent to approximately E10, E14 and E18 in the mouse. Expression of MUL at 4 weeks of gestation was very weak, with some evidence of positive staining in the surface ectoderm lining the branchial arches (data not shown). In 7-week-old embryos, we confirmed that MUL is expressed in several of the aforementioned sites including, dorsal root ganglia, liver, submandibular gland and epithelial lining of the gut lumen (data not shown). In those tissues examined, the expression pattern was the same as in E14.5 mouse embryos. At 10 weeks, the MUL expression pattern correlates with that in mouse embryos, with intense expression in dorsal root and trigeminal ganglia, epithelia in multiple tissues and liver (Fig. 2). In the heart, expression of MUL was not above background levels at the stages we examined in human or mouse (data not shown). In summary, MUL is expressed in multiple locations during mouse and human embryogenesis. These include a subset of neural crest-derived tissues including dorsal root and sympathetic ganglia; MUL is not, however, expressed in migrating neural crest. Other notable sites of expression include the epithelia of several organs whose development is regulated by mesenchymal–epithelial interactions.
2. Experimental procedures In situ hybridisation was carried out using digoxygeninlabelled cRNA probes. The mouse probe was a 371-bp fragment cloned with primers designed from EST vi69g04.r1 sequence (GenBank AA497993) homologous to human MUL, corresponding to nucleotides 683–1053 (GenBank AB020705) of the human MUL cDNA. The human probe was a 483-bp fragment corresponding to nucleotides 546– 1046 (GenBank AB020705). In random bred CD-1 mice, for stages up to E11.5, whole mount in situ hybridisation was carried out according to the method of Wilkinson (1992) with minor modifications (Greene et al., 1998). Older embryos were dehydrated, embedded in paraffin wax and sectioned at 8 mm. Wax embedded sections of human embryos, collected with ethical permission, at 4 weeks ðn ¼ 1Þ, 7 weeks ðn ¼ 2Þ and 10 weeks ðn ¼ 2Þ post-fertilisation were supplied by the MRC/Wellcome Trust Human
Developmental Biology Resource. In situ hybridisation on sections was carried out according to the method of Breitschopf (1992). No staining was detected using sense probes as controls.
Acknowledgements The authors are very grateful to Andrew Copp for providing laboratory space and for helpful discussions. We also thank Jenny Murdoch for critical reading of the manuscript and Paul Winyard for valuable comments. This study was supported by the Wellcome Trust (N.D.E.G.), the British Heart Foundation (V.R.) and the Academy of Finland (A.E.L.), and was partly carried out in the Centre of Excellence in Disease Genetics of the Academy of Finland (Project 44870, Finnish Centre of Excellence Programme 2000– 2005).
References Armstrong, J.F., Pritchard, J.K., Bickmore, W.A., Hastie, N.D., Bard, J.B., 1993. The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo. Mech. Dev. 40, 85–97. Avela, K., Lipsanen-Nyman, M., Ida¨ nheimo, N., Seemanova`, E., Rosengren, S., Ma¨ kela¨ , T.P., Perheentupa, J., de la Chapelle, A., Lehesjoki, A.E., 2000. Gene encoding a new RING-B-box-Coiled-coil protein is mutated in Mulibrey nanism. Nat. Genet. 25, 298–301. Borden, K.L., 2000. RING domains: master builders of molecular scaffolds? J. Mol. Biol. 295, 1103–1112. Breitschopf, H., Suchanek, G., Gould, R.M., Colman, D.R., Lassmann, H., 1992. In situ hybridization with digoxygenin-labeled probes: sensitive and reliable detection method applied to myelinating rat brain. Acta Neuropathol. 84, 581–587. Greene, N.D.E., Gerrelli, D., Van Straaten, H.W.M., Copp, A.J., 1998. Abnormalities of floor plate, notochord and somite differentiation in the loop-tail (Lp) mouse: a model of severe neural tube defects. Mech. Dev. 73, 59–72. Hardy, M.H., 1992. The secret life of the hair follicle. Trends Genet. 8, 55– 61. Hong, Y., Lee, R.C., Ambros, V., 2000. Structure and function analysis of LIN-14, a temporal regulator of postembryonic developmental events in Caenorhabditis elegans. Mol. Cell. Biol. 20, 2285–2295. Lapunzina, P., Rodriguez, J.I., de Matteo, E., Gracia, R., Moreno, F., 1995. Mulibrey nanism: three additional patients and a review of 39 patients. Am. J. Med. Genet. 55, 349–355. Perheentupa, J., Autio, S., Leisti, S., Raitta, C., Tuuteri, L., 1973. Mulibreynanism, an autosomal recessive syndrome with pericardial constriction. Lancet 2, 351–355. Powell, B.C., Passmore, E.A., Nesci, A., Dunn, S.M., 1998. The Notch signalling pathway in hair growth. Mech. Dev. 78, 189–192. Pritchard-Jones, K., 1999. The Wilms tumour gene, WT1, in normal and abnormal nephrogenesis. Pediatr. Nephrol. 13, 620–625. Quaderi, N.A., Schweiger, S., Gaudenz, K., Franco, B., Rugarli, E.I., Berger, W., Feldman, G.J., Volta, M., Andolfi, G., Gilgenkrantz, S., Marion, R.W., Hennekam, R.C., Opitz, J.M., Muenke, M., Ropers, H.H., Ballabio, A., 1997. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat. Genet. 17, 285–291. Scharfmann, R., 2000. Control of early development of the pancreas in rodents and humans: implications of signals from the mesenchyme. Diabetologia 43, 1083–1092.
A.-E. Lehesjoki et al. / Mechanisms of Development 108 (2001) 221–225 Seemanova´ , E., Bartsch, O., 1999. Mulibrey nanism and Wilms’ tumour. Am. J. Med. Genet. 85, 76–78. Simila¨ , S., Timonen, M., Heikkinen, E., 1980. A case of mulibrey nanism with associated Wilms’ tumour. Clin. Genet. 17, 29–30. Spencer, J.A., Eliazer, S., Ilaria, R.L., Richardson, J.A., Olson, E.N., 2000. Regulation of microtubule dynamics and myogenic differentiation by MURF, a striated muscle RING-finger protein. J. Cell Biol. 150, 771– 784.
225
Teitelman, G., Alpert, S., Polak, J.M., Martinez, A., Hanahan, D., 1993. Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development 118, 1031–1039. Wilkinson, D.G., 1992. In situ Hybridisation: A Practical Approach, IRL Press, Oxford.
Gene expression pattern
Expression of MUL, a gene encoding a novel RBCC family ring-finger protein, in human and mouse embryogenesis Anna-Elina Lehesjoki a, Victoria A. Reed b, R. Mark Gardiner c, Nicholas D.E. Greene b,* a
Folkha¨lsan Institute of Genetics and Department of Medical Genetics, Biomedicum Helsinki, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland b Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK c Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK Received 4 April 2001; received in revised form 12 July 2001; accepted 18 July 2001
Abstract We studied the expression of MUL, a gene encoding a novel member of the RING-B-Box-Coiled Coil family of zinc finger proteins that underlies the human inherited disorder, Mulibrey nanism. In early human and mouse embryogenesis MUL is expressed in dorsal root and trigeminal ganglia, liver and in epithelia of multiple tissues. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: MUL; Mulibrey nanism; Ring-finger; RING-B-Box-Coiled Coil protein; Zinc-finger; Wilms tumour; Mouse embryo; Human embryo; Dorsal root ganglia; Trigeminal ganglia; Epithelium; Inherited diseases; Growth retardation
1. Results and discussion Mutations of MUL underlie the autosomal recessive disorder, Mulibrey nanism (for muscle–liver–brain–eye nanism; Avela et al., 2000), which is characterised by prenatal-onset growth failure and pericardial constriction with subsequent hepatomegaly (Perheentupa et al., 1973; Lapunzina et al., 1995). Other features include typical dysmorphic features, J-shaped sella turcica, yellowish dots in the ocular fundi and hypoplasia of various endocrine glands. About 4% of Mulibrey nanism patients develop Wilms tumour (Simila¨ et al., 1980; Seemanova´ and Bartsch, 1999). Northern blot analysis of MUL indicated widespread expression in adult tissues (Avela et al., 2000). MUL encodes a predicted 108 kDa member of the RING-BBox-Coiled-Coil (RBCC) protein family. The RING-finger motif is found in many proteins and has been implicated in mediating protein interactions critical for transcriptional repression and ubiquitination (Borden, 2000). RING fingers may occur in association with other domains, such as the RBCC that characterises a subfamily of zinc finger proteins, the functions of which are largely unknown. Several members of this subfamily play a role in development * Corresponding author. Tel: 144-20-7905-2230; fax: 144-20-78314366. E-mail address: [email protected] (N.D.E. Greene).
including MID1, the gene for X-linked Opitz syndrome, MURF, which acts in skeletal myoblast differentiation in the mouse, and lin-41 in Caenorhabditis elegans (Quaderi et al., 1997; Spencer et al., 2000; Hong et al., 2000). We analysed MUL expression during mouse and human embryogenesis. In mouse, no MUL expression is detected at E8.5 and only very weak, generalised expression is detected at E9.5, E10.5 and E11.5 (data not shown). However, at E11.5 specific staining is also apparent in cells lining the oesophagus and bronchi (Fig. 1A) and in the innermost cells of the optic cup, adjacent to the lens (arrowhead in Fig. 1B). Between E12.5 and E14.5, MUL expression is widespread (Fig. 1). MUL is intensely expressed in the trigeminal and sympathetic ganglia (Fig. 1C,D) and dorsal root ganglia throughout the length of the body axis (Fig. 1D,K). Uniform intense expression is also detected in the liver (Fig. 1D). Among the remaining tissues, MUL expression is frequently localised in epithelia of ectodermal or endodermal origin but is absent from the neuroepithelium and mesothelium. Intense expression is seen in gut epithelium of the midgut (Fig. 1E,K), stomach (data not shown) and oesophagus (Fig. 1F). Expression is also detected in the olfactory epithelium (Fig. 1I), in the epithelial lining of the bronchioles (Fig. 1J), and in the surface ectoderm (Fig. 1D,I). In the developing eye, MUL is expressed in the lens epithelium and the neural layer of the retina but not in the optic nerve (Fig. 1G,H).
0925-4773/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0925-477 3(01)00491-9
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Fig. 1. Expression of MUL in mouse embryogenesis. In situ hybridisation on transverse (A–I,L) and sagittal (J,K,M) sections indicates that MUL is expressed in multiple tissues. At E11.5, expression is detected in oesophagus, bronchi and retina (A,B). At E14.5 (C–M) MUL is expressed in trigeminal (C), dorsal root (D) and sympathetic (arrow in D) ganglia and epithelial cells in several tissues including midgut (E), oesophagus (F), lens (G,H), nasal epithelium (I), bronchioles (J), kidney (K,L). Arrowheads: (B) optic cup cells (future inner layer of retina), (G) lens epithelium, (D,I) surface ectoderm. Arrows: (D) sympathetic ganglion, (E) midgut epithelium, (H) optic nerve, (L) mesonephric duct, (M) vibrissa primordia. Abbreviations: a, primordium of adrenal gland; b, bronchi; d, dorsal root ganglia; e, oesophagus; k, kidney; li, liver; m, mouth; o, olfactory epithelium; p, pancreas; r, retina; s, submandibular gland; t, thyroid; te, testis; to, tongue; tr, trigeminal ganglia; u, upper lip. Scale bar: 0.04 mm (D,F,I–M); 0.02 mm (A–C,E,G,H).
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Fig. 2. Expression of MUL in a human embryo at 10 weeks post-fertilisation. In situ hybridisation on transverse sections (A–H). Intense expression is detected in dorsal root and trigeminal ganglia (A, B), liver (D) and submandibular gland (H) as well as epithelia of several tissues including lens (C), gut (D), bronchioles (E), kidney (F,G), pancreas (G). Arrowhead (C), lens epithelium; arrow (D), midgut epithelium. Abbreviations: d, dorsal root ganglia; k, kidney; li, liver; n, neural tube; p, pancreas; s, submandibular gland; tr, trigeminal ganglia. Scale bar: 0.04 mm (A,C–G); 0.02 mm (B,H).
In the kidney (Fig. 1K,L) MUL expression is detected in the epithelium of the developing nephron, in the commaand s-shaped bodies that are formed following mesenchymal–epithelial transformation of the mesenchyme that condenses around the ureteric bud. Thus, MUL appears to
co-localise, at least partially, with another Wilms tumour associated gene, WT1 (Armstrong, 1993; Pritchard-Jones, 1999). MUL is also expressed in the mesonephric duct (Fig. 1L). In the pancreas, expression is again detected in the epithelial component (Fig. 1E) that includes ductal cells
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that differentiate into mature endocrine and exocrine cells under the control of mesenchymal signals (Teitelman et al., 1993; Scharfmann, 2000). Expression is also evident in the placodes that are the primordia of the vibrissae (Fig. 1M), development of which also depends on epithelial–mesenchymal interactions (Hardy, 1992; Powell et al., 1998). Additional epithelial sites of expression are certain glands, notably the thyroid and submandibular glands (Fig. 1F) and the medulla (but not cortex) of the adrenal glands (Fig. 1K). Intense expression is detected in the primitive seminiferous tubules of the developing testis at E14.5 (Fig. 1L). The expression of MUL in human embryos was examined at 4, 7 and 10 weeks post-fertilisation, equivalent to approximately E10, E14 and E18 in the mouse. Expression of MUL at 4 weeks of gestation was very weak, with some evidence of positive staining in the surface ectoderm lining the branchial arches (data not shown). In 7-week-old embryos, we confirmed that MUL is expressed in several of the aforementioned sites including, dorsal root ganglia, liver, submandibular gland and epithelial lining of the gut lumen (data not shown). In those tissues examined, the expression pattern was the same as in E14.5 mouse embryos. At 10 weeks, the MUL expression pattern correlates with that in mouse embryos, with intense expression in dorsal root and trigeminal ganglia, epithelia in multiple tissues and liver (Fig. 2). In the heart, expression of MUL was not above background levels at the stages we examined in human or mouse (data not shown). In summary, MUL is expressed in multiple locations during mouse and human embryogenesis. These include a subset of neural crest-derived tissues including dorsal root and sympathetic ganglia; MUL is not, however, expressed in migrating neural crest. Other notable sites of expression include the epithelia of several organs whose development is regulated by mesenchymal–epithelial interactions.
2. Experimental procedures In situ hybridisation was carried out using digoxygeninlabelled cRNA probes. The mouse probe was a 371-bp fragment cloned with primers designed from EST vi69g04.r1 sequence (GenBank AA497993) homologous to human MUL, corresponding to nucleotides 683–1053 (GenBank AB020705) of the human MUL cDNA. The human probe was a 483-bp fragment corresponding to nucleotides 546– 1046 (GenBank AB020705). In random bred CD-1 mice, for stages up to E11.5, whole mount in situ hybridisation was carried out according to the method of Wilkinson (1992) with minor modifications (Greene et al., 1998). Older embryos were dehydrated, embedded in paraffin wax and sectioned at 8 mm. Wax embedded sections of human embryos, collected with ethical permission, at 4 weeks ðn ¼ 1Þ, 7 weeks ðn ¼ 2Þ and 10 weeks ðn ¼ 2Þ post-fertilisation were supplied by the MRC/Wellcome Trust Human
Developmental Biology Resource. In situ hybridisation on sections was carried out according to the method of Breitschopf (1992). No staining was detected using sense probes as controls.
Acknowledgements The authors are very grateful to Andrew Copp for providing laboratory space and for helpful discussions. We also thank Jenny Murdoch for critical reading of the manuscript and Paul Winyard for valuable comments. This study was supported by the Wellcome Trust (N.D.E.G.), the British Heart Foundation (V.R.) and the Academy of Finland (A.E.L.), and was partly carried out in the Centre of Excellence in Disease Genetics of the Academy of Finland (Project 44870, Finnish Centre of Excellence Programme 2000– 2005).
References Armstrong, J.F., Pritchard, J.K., Bickmore, W.A., Hastie, N.D., Bard, J.B., 1993. The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo. Mech. Dev. 40, 85–97. Avela, K., Lipsanen-Nyman, M., Ida¨ nheimo, N., Seemanova`, E., Rosengren, S., Ma¨ kela¨ , T.P., Perheentupa, J., de la Chapelle, A., Lehesjoki, A.E., 2000. Gene encoding a new RING-B-box-Coiled-coil protein is mutated in Mulibrey nanism. Nat. Genet. 25, 298–301. Borden, K.L., 2000. RING domains: master builders of molecular scaffolds? J. Mol. Biol. 295, 1103–1112. Breitschopf, H., Suchanek, G., Gould, R.M., Colman, D.R., Lassmann, H., 1992. In situ hybridization with digoxygenin-labeled probes: sensitive and reliable detection method applied to myelinating rat brain. Acta Neuropathol. 84, 581–587. Greene, N.D.E., Gerrelli, D., Van Straaten, H.W.M., Copp, A.J., 1998. Abnormalities of floor plate, notochord and somite differentiation in the loop-tail (Lp) mouse: a model of severe neural tube defects. Mech. Dev. 73, 59–72. Hardy, M.H., 1992. The secret life of the hair follicle. Trends Genet. 8, 55– 61. Hong, Y., Lee, R.C., Ambros, V., 2000. Structure and function analysis of LIN-14, a temporal regulator of postembryonic developmental events in Caenorhabditis elegans. Mol. Cell. Biol. 20, 2285–2295. Lapunzina, P., Rodriguez, J.I., de Matteo, E., Gracia, R., Moreno, F., 1995. Mulibrey nanism: three additional patients and a review of 39 patients. Am. J. Med. Genet. 55, 349–355. Perheentupa, J., Autio, S., Leisti, S., Raitta, C., Tuuteri, L., 1973. Mulibreynanism, an autosomal recessive syndrome with pericardial constriction. Lancet 2, 351–355. Powell, B.C., Passmore, E.A., Nesci, A., Dunn, S.M., 1998. The Notch signalling pathway in hair growth. Mech. Dev. 78, 189–192. Pritchard-Jones, K., 1999. The Wilms tumour gene, WT1, in normal and abnormal nephrogenesis. Pediatr. Nephrol. 13, 620–625. Quaderi, N.A., Schweiger, S., Gaudenz, K., Franco, B., Rugarli, E.I., Berger, W., Feldman, G.J., Volta, M., Andolfi, G., Gilgenkrantz, S., Marion, R.W., Hennekam, R.C., Opitz, J.M., Muenke, M., Ropers, H.H., Ballabio, A., 1997. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat. Genet. 17, 285–291. Scharfmann, R., 2000. Control of early development of the pancreas in rodents and humans: implications of signals from the mesenchyme. Diabetologia 43, 1083–1092.
A.-E. Lehesjoki et al. / Mechanisms of Development 108 (2001) 221–225 Seemanova´ , E., Bartsch, O., 1999. Mulibrey nanism and Wilms’ tumour. Am. J. Med. Genet. 85, 76–78. Simila¨ , S., Timonen, M., Heikkinen, E., 1980. A case of mulibrey nanism with associated Wilms’ tumour. Clin. Genet. 17, 29–30. Spencer, J.A., Eliazer, S., Ilaria, R.L., Richardson, J.A., Olson, E.N., 2000. Regulation of microtubule dynamics and myogenic differentiation by MURF, a striated muscle RING-finger protein. J. Cell Biol. 150, 771– 784.
225
Teitelman, G., Alpert, S., Polak, J.M., Martinez, A., Hanahan, D., 1993. Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development 118, 1031–1039. Wilkinson, D.G., 1992. In situ Hybridisation: A Practical Approach, IRL Press, Oxford.