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Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL - Nat. Genet. (2011)

Bottom Line: Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities.Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration.Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Unit, University College London Institute of Child Health, London, UK.

ABSTRACT
3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

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a. SOX10/MyoD in situ experiments on zebrafish colec11 and masp1 morphants showing an abnormal distribution of the CNCC in the hindbrain of 10 somite-stage embryos, with a massive expansion of cells across the midline compared to controls (left panel, white arrowheads). b. Streaming of NCCs into the head and through the somites (arrow heads) is also disrupted in colec11 and masp1 morphants at 24 hpf, as indicated by aberrant sox10 expression. (scale bar: main panels 200 μm, inset panels 100 μm) c. Expression of Sox10:eGFP (green) in the head at 24 hpf highlights disorganised NCCs in colec11 and masp1 morphants (scale bar: 100 μm). d. At 48 hpf, clearly defined tracks of Sox10:eGFP (white arrow heads) are detected migrating through tail somites of uninjected control embryos, however both colec11 and masp1 morphants show abnormal and ectopic migration of NCCs throughout the tail. Scale bar: 100 μm.
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Figure 5: a. SOX10/MyoD in situ experiments on zebrafish colec11 and masp1 morphants showing an abnormal distribution of the CNCC in the hindbrain of 10 somite-stage embryos, with a massive expansion of cells across the midline compared to controls (left panel, white arrowheads). b. Streaming of NCCs into the head and through the somites (arrow heads) is also disrupted in colec11 and masp1 morphants at 24 hpf, as indicated by aberrant sox10 expression. (scale bar: main panels 200 μm, inset panels 100 μm) c. Expression of Sox10:eGFP (green) in the head at 24 hpf highlights disorganised NCCs in colec11 and masp1 morphants (scale bar: 100 μm). d. At 48 hpf, clearly defined tracks of Sox10:eGFP (white arrow heads) are detected migrating through tail somites of uninjected control embryos, however both colec11 and masp1 morphants show abnormal and ectopic migration of NCCs throughout the tail. Scale bar: 100 μm.

Mentions: Owing to the pigmentation defect observed in the zebrafish morphants, and because the majority of the head skeleton derives from cranial neural crest cells (CNCC) that migrate from the dorsal aspect of the neural tube into the frontonasal process and the pharyngeal arches, we next investigated whether CL-K1 and MASP-1 proteins were involved in CNCC migration. We performed sox10 in situ hybridization in colec11 and masp1 zebrafish morphant embryos at 10 somites and 24 hpf respectively. An abnormal distribution of the CNCC in the hindbrain was observed in 10 somite-stage embryos with massive expansion of cells across the midline compared to controls (Fig 5a). At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the colec11 morphants and obviously truncated in the masp1 morphants (Fig 5b). In addition, we injected SOX10-eGFP zebrafish with colec11 and masp1 MO and observed at 48 hpf, ectopic NCC in the head, trunk and periphery (Fig 5c,d). Together these data suggest that CL-K1 and MASP-1 likely behave as early guidance cues to direct the migration of neural crest cells during embryonic development.


Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL - Nat. Genet. (2011)

a. SOX10/MyoD in situ experiments on zebrafish colec11 and masp1 morphants showing an abnormal distribution of the CNCC in the hindbrain of 10 somite-stage embryos, with a massive expansion of cells across the midline compared to controls (left panel, white arrowheads). b. Streaming of NCCs into the head and through the somites (arrow heads) is also disrupted in colec11 and masp1 morphants at 24 hpf, as indicated by aberrant sox10 expression. (scale bar: main panels 200 μm, inset panels 100 μm) c. Expression of Sox10:eGFP (green) in the head at 24 hpf highlights disorganised NCCs in colec11 and masp1 morphants (scale bar: 100 μm). d. At 48 hpf, clearly defined tracks of Sox10:eGFP (white arrow heads) are detected migrating through tail somites of uninjected control embryos, however both colec11 and masp1 morphants show abnormal and ectopic migration of NCCs throughout the tail. Scale bar: 100 μm.
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Related In: Results  -  Collection

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Figure 5: a. SOX10/MyoD in situ experiments on zebrafish colec11 and masp1 morphants showing an abnormal distribution of the CNCC in the hindbrain of 10 somite-stage embryos, with a massive expansion of cells across the midline compared to controls (left panel, white arrowheads). b. Streaming of NCCs into the head and through the somites (arrow heads) is also disrupted in colec11 and masp1 morphants at 24 hpf, as indicated by aberrant sox10 expression. (scale bar: main panels 200 μm, inset panels 100 μm) c. Expression of Sox10:eGFP (green) in the head at 24 hpf highlights disorganised NCCs in colec11 and masp1 morphants (scale bar: 100 μm). d. At 48 hpf, clearly defined tracks of Sox10:eGFP (white arrow heads) are detected migrating through tail somites of uninjected control embryos, however both colec11 and masp1 morphants show abnormal and ectopic migration of NCCs throughout the tail. Scale bar: 100 μm.
Mentions: Owing to the pigmentation defect observed in the zebrafish morphants, and because the majority of the head skeleton derives from cranial neural crest cells (CNCC) that migrate from the dorsal aspect of the neural tube into the frontonasal process and the pharyngeal arches, we next investigated whether CL-K1 and MASP-1 proteins were involved in CNCC migration. We performed sox10 in situ hybridization in colec11 and masp1 zebrafish morphant embryos at 10 somites and 24 hpf respectively. An abnormal distribution of the CNCC in the hindbrain was observed in 10 somite-stage embryos with massive expansion of cells across the midline compared to controls (Fig 5a). At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the colec11 morphants and obviously truncated in the masp1 morphants (Fig 5b). In addition, we injected SOX10-eGFP zebrafish with colec11 and masp1 MO and observed at 48 hpf, ectopic NCC in the head, trunk and periphery (Fig 5c,d). Together these data suggest that CL-K1 and MASP-1 likely behave as early guidance cues to direct the migration of neural crest cells during embryonic development.

Bottom Line: Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities.Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration.Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Unit, University College London Institute of Child Health, London, UK.

ABSTRACT
3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

Show MeSH
Related in: MedlinePlus