Abstract
Methyl-CpG binding domain protein 5 (MBD5) belongs to the MBD family proteins, which play central roles in transcriptional regulation and development. The significance of MBD5 function is highlighted by recent studies implicating it as a candidate gene involved in human 2q23.1 microdeletion syndrome. To investigate the physiological role of Mbd5, we generated knockout mice. The Mbd5-deficient mice showed growth retardation, wasting and pre-weaning lethality. The observed growth retardation was associated with the impairment of GH/IGF-1 axis in Mbd5-null pups. Conditional knockout of Mbd5 in the brain resulted in the similar phenotypes as whole body deletion, indicating that Mbd5 functions in the nervous system to regulate postnatal growth. Moreover, the mutant mice also displayed enhanced glucose tolerance and elevated insulin sensitivity as a result of increased insulin signaling, ultimately resulting in disturbed glucose homeostasis and hypoglycemia. These results indicate Mbd5 as an essential factor for mouse postnatal growth and maintenance of glucose homeostasis.
Highlights
In vertebrates, cytosine methylation in DNA is one of the major epigenetic modifications, which regulates many cellular events, including developmental gene expression, X chromosome inactivation, genome defense, and genomic imprinting [1]
The genotypes of all mice were confirmed by PCR (Figure 1C) and the absence of full-length Mbd5 mRNA in homozygous mutants was confirmed in various tissues by RT-PCR analysis (Figure 1D)
We identified the in vivo function of a novel methylCpG binding domain (MBD) family protein, Methyl-CpG binding domain protein 5 (MBD5), in mice
Summary
Cytosine methylation in DNA is one of the major epigenetic modifications, which regulates many cellular events, including developmental gene expression, X chromosome inactivation, genome defense, and genomic imprinting [1]. Five mammalian MBD family proteins, MeCP2, MBD1, MBD2, MBD3 and MBD4, have been well characterized These proteins, except for MBD3, bind selectively to methylated DNA [3,4] and play roles in transcriptional repression and chromatin remodeling [5,6,7]. The developmental significance of MBD proteins in interpreting DNA methylation patterns and mediating transcriptional repression has been demonstrated mainly in human congenital disorders and knockout mouse models [8]. Based on the presence of the MBD and PWWP domains in the encoded protein and the association of MBD5 mutation with human mental retardation, we hypothesized that MBD5 plays a unique role during development
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