Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development

Nature Genetics volume 44, pages 1260–1264 (2012)Cite this article

Subjects

Abstract

Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex1,2 but is also suggested to localize to the nuclear matrix and regulate chromatin structure3. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Brain MRI and linkage mapping of pontocerebellar hypoplasia with microcephaly.
Figure 2: Loss-of-function mutations in CHMP1A and dysregulation of INK4A in cell lines from affected individuals.
Figure 3: Genetic links between CHMP1A and BMI1 in zebrafish and mice.
Figure 4: CHMP1A and BMI1 expression in cultured cells and the developing mouse brain.

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Howard, T.L., Stauffer, D.R., Degnin, C.R. & Hollenberg, S.M. CHMP1 functions as a member of a newly defined family of vesicle trafficking proteins. J. Cell Sci. 114, 2395–2404 (2001).

    CAS  PubMed  Google Scholar 

  2. Tsang, H.T. et al. A systematic analysis of human CHMP protein interactions: additional MIT domain–containing proteins bind to multiple components of the human ESCRT III complex. Genomics 88, 333–346 (2006).

    Article  CAS  Google Scholar 

  3. Stauffer, D.R., Howard, T.L., Nyun, T. & Hollenberg, S.M. CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression. J. Cell Sci. 114, 2383–2393 (2001).

    CAS  PubMed  Google Scholar 

  4. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  5. Stuchell-Brereton, M.D. et al. ESCRT-III recognition by VPS4 ATPases. Nature 449, 740–744 (2007).

    Article  CAS  Google Scholar 

  6. Scita, G. & Di Fiore, P.P. The endocytic matrix. Nature 463, 464–473 (2010).

    Article  CAS  Google Scholar 

  7. Molofsky, A.V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  Google Scholar 

  8. Garel, C., Fallet-Bianco, C. & Guibaud, L. The fetal cerebellum: development and common malformations. J. Child Neurol. 26, 1483–1492 (2011).

    Article  Google Scholar 

  9. Jacobs, J.J., Kieboom, K., Marino, S., DePinho, R.A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

    Article  CAS  Google Scholar 

  10. Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004).

    Article  CAS  Google Scholar 

  11. van der Lugt, N.M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994).

    Article  CAS  Google Scholar 

  12. Zencak, D. et al. Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J. Neurosci. 25, 5774–5783 (2005).

    Article  CAS  Google Scholar 

  13. Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    Article  CAS  Google Scholar 

  14. Gudbjartsson, D.F., Jonasson, K., Frigge, M.L. & Kong, A. Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13 (2000).

    Article  CAS  Google Scholar 

  15. Rozen, S. & Skaletsky, H.J. Primer3 on the WWW for general users and for biologist programmers. in Bioinformatics Methods and Protocols: Methods in Molecular Biology (eds. Krawetz, S. & Misener, S.) 365–386 (Humana Press, Totowa, New Jersey, 2000).

  16. Brunak, S., Engelbrecht, J. & Knudsen, S. Prediction of human mRNA donor and acceptor sites from the DNA sequence. J. Mol. Biol. 220, 49–65 (1991).

    Article  CAS  Google Scholar 

  17. Flavell, S.W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity–dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008).

    Article  CAS  Google Scholar 

  18. Kimmel, C.B., Ballard, W.W., Kimmel, S.R., Ullmann, B. & Schilling, T.F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253–310 (1995).

    Article  CAS  Google Scholar 

  19. Link, V., Shevchenko, A. & Heisenberg, C.P. Proteomics of early zebrafish embryos. BMC Dev. Biol. 6, 1 (2006).

    Article  Google Scholar 

  20. Bilimoria, P.M. & Bonni, A. Cultures of cerebellar granule neurons. CSH Protoc. 2008, pdb prot5107 (2008).

Download references

Acknowledgements

We thank the individuals and their families reported herein for their participation in this research. We thank M. van Lohuizen (Netherlands Cancer Institute) for providing the Bmi1-knockout mice, A. Wagers for help with breeding the Bmi1-knockout mice and P. Baas for sharing human DNA samples. This research was supported by grants from the US National Institute of Neurological Disorders and Stroke (NINDS; R01NS035129) and the Fogarty International Center (R21TW008223) to C.A.W., the Dubai Harvard Foundation for Medical Research, the Simons Foundation and the Manton Center for Orphan Disease Research. G.H.M. was supported by the Young Investigator Award of the National Alliance for Research on Schizophrenia and Depression (NARSAD) as a NARSAD Lieber Investigator. V.S.G. is supported by the Medical Scientist Training Program of Harvard Medical School, with financial support from the US National institute of General Medical Sciences (NIGMS). C.A.W. and L.I.Z. are investigators of the Howard Hughes Medical Institute. Microscopy and image analyses were performed with support from the Cellular Imaging Core of the Boston Children's Hospital Intellectual and Developmental Disabilities Research Center.

Author information

Author notes

  1. Ganeshwaran H Mochida and Vijay S Ganesh: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Medicine, Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA

    Ganeshwaran H Mochida, Vijay S Ganesh, Kutay D Atabay, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Brenda J Barry, Jennifer N Partlow, Wen-Hann Tan & Christopher A Walsh

  2. Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA

    Ganeshwaran H Mochida, Vijay S Ganesh, Kutay D Atabay, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Brenda J Barry, Jennifer N Partlow & Christopher A Walsh

  3. Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA

    Ganeshwaran H Mochida, Vijay S Ganesh, Kutay D Atabay, Katie L Kathrein, Hsuan-Ting Huang, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Brenda J Barry, Jennifer N Partlow, Leonard I Zon & Christopher A Walsh

  4. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

    Ganeshwaran H Mochida, Wen-Hann Tan, Laurie J Glader, Leonard I Zon & Christopher A Walsh

  5. Department of Neurology, Pediatric Neurology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

    Ganeshwaran H Mochida

  6. Harvard–Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, Massachusetts, USA

    Vijay S Ganesh & Athar N Malik

  7. Department of Morphologic Sciences, Cayetano Heredia University, Lima, Peru

    Maria I de Michelena

  8. Institute for Child Development–ARIE, Lima, Peru

    Hugo Dias

  9. Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA

    Katie L Kathrein, Hsuan-Ting Huang & Leonard I Zon

  10. Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA

    Katie L Kathrein, Hsuan-Ting Huang & Leonard I Zon

  11. Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Katie L Kathrein, Hsuan-Ting Huang & Leonard I Zon

  12. Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA

    Anthony D Hill

  13. Division of General Pediatrics, Complex Care Service, Boston Children's Hospital, Boston, Massachusetts, USA

    Laurie J Glader

  14. Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.,

    A James Barkovich

  15. Center for Integrative Brain Research, University of Washington, Seattle, Washington, USA

    William B Dobyns

  16. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    Leonard I Zon

  17. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA

    Christopher A Walsh

Authors
  1. Ganeshwaran H Mochida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vijay S Ganesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria I de Michelena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugo Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kutay D Atabay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katie L Kathrein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hsuan-Ting Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R Sean Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jillian M Felie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel Rakiec
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Danielle Gleason
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anthony D Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Athar N Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Brenda J Barry
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jennifer N Partlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Wen-Hann Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Laurie J Glader
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. A James Barkovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. William B Dobyns
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Leonard I Zon
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Christopher A Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.H.M. designed the study, interpreted clinical information and brain MRIs, identified the disease locus, helped sequence candidate genes, analyzed the sequencing data to identify CHMP1A mutations, helped analyze the functional data and wrote the manuscript. V.S.G. performed RT-PCR, protein blots, mouse histology and immunohistochemistry, qPCR, ChIP and zebrafish morpholino experiments and wrote the manuscript. M.I.d.M. and H.D. ascertained family 1 and provided clinical information. K.D.A. performed zebrafish protein blots and mouse immunohistochemistry. K.L.K. performed the morpholino injections. H.-T.H. and L.I.Z. assisted with the morpholino experiments. R.S.H. helped organize genetic data and calculate LOD scores. J.M.F. and D.G. organized human samples and helped perform sequencing experiments. D.R. organized human samples and helped perform microsatellite analysis. A.D.H. assisted in immunohistochemical studies and imaging. A.N.M. assisted in ChIP. B.J.B. and J.N.P. organized clinical information and human samples. W.-H.T. and L.J.G. provided clinical information for family 3. A.J.B. interpreted the brain MRIs of the affected individuals. W.B.D. ascertained family 2 and provided clinical information. C.A.W. directed the overall research and wrote the manuscript.

Corresponding author

Correspondence to Christopher A Walsh.

Ethics declarations

Competing interests

L.I.Z. is a founder and stockholder of Fate Therapeutics, Inc., and a scientific advisor for Stemgent.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Note (PDF 4341 kb)

Supplementary Video 1

Brain MRI of CH2402. T1-weighted sagittal sequence reveals a very small cerebellum (vermis and hemispheres) and pons. There is no malformation of the cerebral cortex but the cerebral white matter volume is severely reduced with a fully formed but thin corpus callosum. (MOV 907 kb)

Supplementary Video 2

Brain MRI of CH3102. T1-weighted saggital sequence shows a very small cerebellum (vermis and hemispheres), and pons. There is no malformation of the cerebral cortex but the cerebral white matter is moderately diminished in volume with a fully formed but thin corpus callosum. (MOV 1752 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mochida, G., Ganesh, V., de Michelena, M. et al. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet 44, 1260–1264 (2012). https://doi.org/10.1038/ng.2425

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2425

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing