博文
《自然》：鱼的脑袋和人的疾病
|||
Neurodevelopmental and neuropsychiatric disorders can be caused by a multitude of genetic and environmental factors. The genetic abnormalities associated with disorders such as autism, schizophrenia and early-onset bipolar disorder1 include a class of mutations called copy-number variants (CNVs), which involve deletion or duplication of whole regions of the genome, typically spanning multiple genes. Among the CNVs most frequently observed in psychiatric disorders is a region of chromosome 16 that contains 29 genes2, 3, called 16p11.2. However, we still have little understanding of the mechanism by which this CNV exerts its clinical effects, and, indeed, which gene or genes are responsible. On page 363 of this issue, Golzio and colleagues show4 that one of the 16p11.2 CNV genes, KCTD13, helps to regulate brain size in zebrafish. This finding provides a tantalizing potential link between KCTD13 and the abnormalities in brain growth and behaviour that are associated with the 16p11.2 CNV in humans.
At the genetic level, the 16p11.2 CNV comes in two forms: a deletion and a duplication, each of the same 29 genes. The associated clinical presentation of patients can be quite variable, but some human traits have been found to correlate strongly with CNV genotype. Patients with the deletion can show obesity5, 6 and increased head size7, 8, whereas the duplication is associated with leanness9, decreased head size7, 8 and psychiatric disorders8. Both the loss and the gain of 16p11.2 confer a significant risk of autism10 and developmental delay2, 7.
Because CNVs can span multiple genes, their effects could be due to the loss or gain of either a single gene or a combination of multiple genes, which makes it difficult to study CNVs in animal model systems. A new chromosome-engineered mouse model has faithfully recapitulated the human genotype and some of the human clinical characteristics associated with the 16p11.2 CNV. Most notably, this model has shown11 that the 16p11.2 CNV has similar effects on head size in humans and mice. But these models have not pinpointed the effects of individual genes.
The success of Golzio and colleagues' strategy can be attributed to their use of the zebrafish as an efficient tool for genetic manipulation and high-throughput screening. Attempting to model psychiatric conditions in fish presents obvious challenges, but the authors overcome some of these difficulties by focusing on the anatomical feature of brain size, which can be readily ascertained in fish.
The researchers show that, in zebrafish, the overexpression of a single gene, KCTD13, causes a significant decrease in brain size (microcephaly), whereas inhibition of KCTD13 expression leads to an increase in brain size (macrocephaly). These changes perfectly mirror the effects of the 16p11.2 CNV on head size in humans and mice8, 11.
KCTD13 expression levels seem to influence brain growth by regulating neuron cell number during development. When Golzio and colleagues measured the rates of proliferation and death among neuronal progenitor cells in zebrafish and mice, they found that the KCTD13 dosage modulates early neurogenesis, or neuron formation. Increased KCTD13 expression induces programmed cell death of neuronal progenitors, whereas decreased expression leads to increased progenitor-cell proliferation (Fig. 1).
Golzio et al.4 show that overexpression of a single gene, KCTD13, causes abnormally small head size in zebrafish embryos, and that inhibition of the gene leads to oversized heads. This effect apparently arises from the KCTD13 protein's influence on the growth of neural progenitor cells — the protein's presence leads to cell death, but in its absence cell proliferation is enhanced. The authors also show that the expression level of two of KCTD13's neighbouring genes, MVP and MAPK3, enhance the effect of KCTD13 on fish head size. All three genes belong to the 16p11.2 copy-number variant, a mutation that is associated with abnormal brain growth and neurodevelopmental disorders in humans.
These findings suggest that KCTD13 is responsible for the abnormalities in brain growth associated with 16p11.2 copy number. However, KCTD13 may not be the only gene involved. By performing pairwise overexpressions of KCTD13 with each of the remaining 16p11.2 genes, the authors show that two other genes — MAPK3 and MVP — interact with KCTD13 to increase its influence on brain size.
Is KCTD13 a key gene for autism risk in humans? Although plausible, this possibility has not been confirmed, and genetic evidence from humans is still largely anecdotal. This study and a previous one12 identified two individuals with autism who had small deletions of KCTD13, but confirming the role of KCTD13 in autism and related disorders will require additional studies in humans and in mice.
The function of the protein encoded by KCTD13 is unclear. It is known13 that KCTD13 interacts directly with a protein called proliferating cell nuclear antigen (PCNA), which is involved in numerous cell processes including DNA replication and repair, and the assembly of chromatin — the DNA–protein complex that makes up the chromosome. This activity is consistent with KCTD13 having a role in the regulation of the cell cycle. Intriguingly, the proteins encoded by MAPK3 and MVP — the two genes that were found to interact with KCTD13 — also regulate cell proliferation14, 15. Thus, Golzio and colleagues' findings allow for a speculative but coherent model of the molecular, cellular and neuroanatomical mechanism of disease in autism: changes in the number of copies of KCTD13, MAPK3 and MVP directly affect cell-cycle regulation and cell proliferation, thereby leading to abnormal brain growth. This notion is supported by the existence of other brain-overgrowth syndromes in humans that are also associated with mutations in genes that control cell-cycle progression16, including tuberous sclerosis, neurofibromatosis, Cowden syndrome and Sotos syndrome.
Golzio and colleagues' use of the zebrafish, the little aquarium fish originally from the River Ganges, has provided a big clue to the molecular and cellular mechanisms underlying the conditions associated with the 16p11.2 CNV. Similar studies might prove effective in elucidating the relationship between genes and neurodevelopment in other genetic disorders and in complex inherited disease.
References
- & Cell 148, 1223–1241 (2012).
- et al. Nature Genet. 43, 838–846 (2011).
- et al. Genet. Med. 13, 777–784 (2011).
- et al. Nature 485, 363–367 (2012). <SPAN class=Z3988 title="ctx_ver=Z39.88-2004&rft_id=info:doi/10.1038/nature11091&rft_id=info:pmid/{pubmed}&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.aulast=Golzio&rft.aufirst=C.&rft.jtitle=Nature&rft.volume=485&rft.spage=363&rft.epage=367&rft.date=2012&rft.atitle=KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant&rfr_id=info:sid/nature.com:Nature.com&id=doi:10.1038/nature11091&id=pmid:{pubmed}&genre=article&aulast=Golzio&aufirst=C.&title=Nature&volume=485&spage=363&epage=367&date=2012&atitle=KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant&sid=nature:Nature">
- et al. Nature 463, 666–670 (2010).
- et al. Nature 463, 671–675 (2010).
- et al. J. Med. Genet. 47, 332–341 (2010).
- et al. Nature Genet. 41, 1223–1227 (2009).
- et al. Nature 478, 97–102 (2011).
- et al. N. Engl. J. Med. 358, 667–675 (2008).
- et al. Proc. Natl Acad. Sci. USA 108, 17076–17081 (2011).
- et al. Am. J. Med. Genet. B 156, 243–245 (2011).
- , , & Proc. Natl Acad. Sci. USA 98, 11979–11984 (2001).
- et al. Nature Med. 1, 578–582 (1995).
- & Cell Res. 12, 9–18 (2002).
- Jr Am. J. Med. Genet. C 117, 49–56 (2003).
http://www.nature.com/nature/journal/v485/n7398/full/485318a.html#/references
https://wap.sciencenet.cn/blog-5414-571781.html
上一篇：美中合作研究表明北京奥运会控制空气污染改善了人民心血管健康
下一篇：“好”胆固醇未必真好
