Biological Consequences of Divergent Evolution of M6P/IGF2R Imprinting

Randy Jirtle
Department of Oncology; University of Wisconsin-Madison

The M6P/IGF2R (Mannose 6-Phosphate/Insulin-like Growth Factor 2 Receptor) encodes for a 275 kDa monomeric multifunctional transmembrane binding receptor that lacks intrinsic tyrosine kinase activity. Thus, the mitogenic effects of IGF2 are mediated through the IGF1R and the insulin receptor isoform A, not the M6P/IGF2R. High affinity binding sites for phosphomannosyl glycoproteins, IGF2 and retinoic acid, and independent lower affinity binding sites for plasminogen and uPAR (urokinase-type plasminogen activator receptor) are contained in the large extracellular portion of the M6P/IGF2R [1]. Consequently, this multifunctional tumor suppressor affects normal growth and development by trafficking lysosomal enzymes from the trans-Golgi network to the lysosomes, regulating the extracellular bioavailability of growth factors such as TGF� and IGF2, and facilitating neurotransmitter release [1].

The M6P/IGF2R is also imprinted with preferential suppression of the paternal allele occurring about 180 million years ago in a common ancestor to marsupials and eutherian mammals [2]. Thus, imprinting at this locus evolved in mammals with the advent of viviparity. We have now shown that the opossum M6P/IGF2R is imprinted not only in peripheral tissues, but also in the brain. In contrast, the M6P/IGF2R is biallelically expressed in the brains of eutherian mammals such as mice and humans, an effect that appears to be neuron-specific [3]. In the Euarchonta clade of mammals which includes humans, M6P/IGF2R imprinting is also lost in peripheral tissues [4].

In this study, we used the M6p/Igf2r floxed mouse that we produced [5] to determine if monoallelic expression of this receptor in the brain affects cognitive ability. We demonstrated that M6p/Igf2r haploinsufficiency results in a male-specific impairment in cognitive function as measured with an eight-arm radial maze win-shift task. Moreover, inheritance of a nonsynonymous polymorphism in the human M6P/IGF2R that significantly reduces receptor stability is also strongly associated with reduced IQ in males, but not in females. These findings suggest the intriguing possibility that M6p/Igf2r loss of imprinting in the brain of an ancestor common to eutherians may have provided early placental mammals with a cognitive edge. (Supported by NIH grants CA25951, ES08823 and ES13053)


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  2. Killian, J.K., Byrd, J.C, Jirtle, J.V., Munday, B.L., Stoskopf, M.K., and Jirtle, R.L. M6P/IGF2R imprinting evolution in mammals. Mol. Cell 5: 707-716, 2000.

  3. Yamasaki ,Y., Kayashima, T., Soejima, H., Kinoshita, A., Yoshiura, K., Matsumoto, N., Ohta, T., Urano, T., Masuzaki, H., Ishimaru, T., Mukai, T., Niikawa, N., and Kishino, T. Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. Hum. Mol. Genet. 14: 2511-2520, 2005

  4. Killian, J.K., Nolan C.M., Wylie A.A., Li T., Vu T.H., Hoffman A.R., and Jirtle, R.L. Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary. Hum. Mol. Genet. 10: 1721-1728, 2001.

  5. Wylie, A.A., Pulford, D.J., McVie-Wylie, A.J., Waterland, R.A., Evans, H.K., Chen, Y.T., Nolan, C.M., Orton, T.C., and Jirtle, R.L. Tissue-specific inactivation of murine M6P/IGF2R. Am. J. Pathol. 162: 321-328, 2003.