Imprinted genes and neuroendocrine function

doi:10.1016/j.yfrne.2007.12.001

Frontiers in Neuroendocrinology

Volume 29, Issue 3, June 2008, Pages 413-427

https://doi.org/10.1016/j.yfrne.2007.12.001 Get rights and content

Abstract

Imprinted genes are monoallelically expressed in a parent-of-origin dependent manner. Whilst the full functional repertoire of these genes remains obscure, they are generally highly expressed in the brain and are often involved in fundamental neural processes. Besides influencing brain neurochemistry, imprinted genes are important in the development and function of the hypothalamus and pituitary gland, key sites of neuroendocrine regulation. Moreover, imprinted genes may directly modulate hormone-dependent signalling cascades, both in the brain and elsewhere. Much of our knowledge about imprinted gene function has come from studying knockout mice and human disorders of imprinting. One such disorder is Prader–Willi syndrome, a neuroendocrine disorder characterised by hypothalamic abnormalities and aberrant feeding behaviour. Through examining the role of imprinted genes in neuroendocrine function, it may be possible to shed light on the neurobiological basis of feeding and aspects of social behaviour and underlying cognition, and to provide insights into disorders where these functions go awry.

Section snippets

An introduction to imprinted genes

Imprinted genes differ from the majority of mammalian genes in that whilst they are inherited in duplicate (one allele from either parent), only one allele is expressed (Fig. 1)[132]. For some imprinted genes it is the paternally inherited allele which is preferentially expressed, and these genes are known as ‘paternally expressed genes’. For the remainder, the maternally inherited allele is preferentially expressed, and these are, logically enough, referred to as ‘maternally expressed genes’.

Imprinting in the brain

The vast majority (perhaps as high as 90%) of imprinted genes are highly expressed in the brain [39]. Imprinted gene expression in this tissue is regulated epigenetically in a highly spatiotemporally dynamic manner, with some genes being imprinted only at certain developmental timepoints, and others being imprinted only in specific brain regions, or cell types. Several lines of evidence, predominantly from mouse models, have suggested key roles for imprinted genes in neurodevelopmental

Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder arising due to the lack of paternally expressed gene product from the imprinted gene-rich region of chromosome 15q11-q13 [51]. Three types of cytogenetic abnormality may result in this lack of paternal gene product: firstly, and most commonly, a deletion on the paternally inherited chromosome; secondly, uniparental disomy for the maternal chromosomal region (mUPD), and thirdly, and least commonly, a mutation in the so-called

Mouse models of PWS

Whilst various early mouse models managed to recapitulate aspects of the PWS phenotype, it is not until very recently that a mouse model has been produced that seems to model the core phenotype of adult feeding abnormalities with associated weight gain. Like PWS subjects, Magel2–null mice exhibit mild neonatal growth retardation, excessive weight gain after weaning and increased adiposity with altered metabolism in adulthood [8]; these mice also exhibit aberrant circadian rhythm output

Neuroendocrine abnormalities in other imprinted disorders

Whilst PWS is perhaps the best defined imprinted gene disorder in terms of its behavioural and neuroendocrinological manifestations, a number of other syndromes associated with imprinted gene dysregulation can present with endocrine sequelae. These include Albright’s heriditary osteodystrophy, pseudohypoparathyroidism, Beckwith–Wiedemann syndrome and diabetes [128]. Here, we limit our discussion to syndromes in which cognitive abnormalities are prominent features. Interestingly, the

Interactions between imprinted genes and gonadal hormones

The neuroanatomical phenotype of TS may represent the upshot of a complex series of interactions between X-linked imprinted genes and hormones. Explicit evidence that imprinted gene products may directly affect hormonal function has come from studying the protein encoded by the maternally expressed Ube3a gene. The protein encoded by this gene (referred to as Ube3a or E6-associated protein (E6-AP)) has been well studied in terms of its molecular interactions. It has been shown to comprise two

Imprinted genes and brain neurochemistry

Due to the comparative rarity of human imprinted disorders and the lack of post mortem brain tissue associated with them, much of our knowledge about the neurochemical systems influenced by imprinted genes has come from experimental systems (cell culture and rodent models) or through the analysis of surrogate tissues such as blood. These studies have revealed that the majority of imprinted genes are widely expressed throughout the brain, and are likely to influence multiple systems [39].

The Gnas locus as a paradigm for endocrine effects

Early work comparing mice disomic for maternally inherited chromosome 2 to those paternally disomic for the same chromosome, provided a powerful demonstration of the pervasive, and reciprocal nature of parent-of-origin effects mediated by imprinted genes [25]. Briefly, mice inheriting both copies of chromosome 2 from their mother tended to be hypokinetic and failed to suckle, whilst mice inheriting both copies of chromosome 2 from their father tended to be hyperkinetic. Both groups of mice died

Summary and outstanding questions

It is less than 20 years since the first imprinted genes were identified. In that time, we have identified many more imprinted genes across a number of species, and we have made substantial progress in understanding the epigenetic basis of their regulation. However, we currently know relatively little about how imprinted genes function at the molecular and systems levels, and about how and why evolution has chosen their expression to be controlled in such an idiosyncratic manner. The

Acknowledgements

WD is a Research Councils UK (RCUK) Fellow in Translational Research in Experimental Medicine and was supported by a Wellcome Trust ‘Value in People’ Award. PMYL is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) UK. DR is supported by a Dorothy Hodgkin Postgraduate Award. LSW is a member of the Medical Research Council (MRC) Cooperative on Imprinting in Health and Disease.

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ReviewImprinted genes and neuroendocrine function

Abstract

Section snippets

An introduction to imprinted genes

Imprinting in the brain

Prader–Willi syndrome

Mouse models of PWS

Neuroendocrine abnormalities in other imprinted disorders

Interactions between imprinted genes and gonadal hormones

Imprinted genes and brain neurochemistry

The Gnas locus as a paradigm for endocrine effects

Summary and outstanding questions

Acknowledgements

Biol. Psychiat.

Neuropsychologia

Curr. Opin. Genet. Dev.

Lancet

Brain Res. Mol. Brain Res.

Exp. Neurol.

Biol. Psychiat.

Neurosci. Biobehav. Rev.

Psychiat. Res.

Biol. Psychiat.

Eur. J. Pharmacol.

Brain Res. Mol. Brain Res.

Trends Endocr. Met.

Am. J. Clin. Nutr.

J. Theor. Biol.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Trends Genet.

Neuron

Genomics

Biol. Psychiat.

Dev. Biol.

Gene Expr. Patterns

J. Biol. Chem.

Brain Res. Dev. Brain Res.

Horm. Behav.

Neurosci. Lett.

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death

BMC Dev. Biol.

Silver–Russell syndrome. Observations in 20 patients

Helv. Paediatr. Acta

Regulation of placental efficiency for nutrient transport by imprinted genes

Placenta

Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism

J. Evol. Biol.

Sex differences in the brain: implications for explaining autism

Science

The neuroscience of affiliation: forging links between basic and clinical research on neuropeptides and social behavior

Horm. Behav.

Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader–Willi syndrome

Hum. Mol. Genet.

Whole genome microarray analysis of gene expression in Prader–Willi syndrome

Am. J. Med. Genet. A

Beyond hormones: a novel hypothesis for the biological basis of male sexual orientation

J. Endocrinol. Invest.

Care of girls and women with Turner syndrome: A guideline of the Turner syndrome study group

J. Clin. Endocrinol. Met.

Peripheral markers of the gamma-aminobutyric acid (GABA)ergic system in Angelman’s syndrome

J. Child Neurol.

Possible parent-of-origin effect of Dopa decarboxylase in susceptibility to bipolar affective disorder

Am. J. Med. Genet. B Neuropsychiatr. Genet.

The Prader–Willi syndrome: a study of 40 patients and a review of the literature

Medicine (Baltimore)

Plasma obestatin and ghrelin levels in subjects with Prader–Willi syndrome

Am. J. Med. Genet. A

Plasma peptide YY and ghrelin levels in infants and children with Prader–Willi syndrome

J. Pediatr. Endocr. Met.

Comparison of leptin protein levels in Prader–Willi syndrome and control individuals

Am. J. Med. Genet.

Effects of growth hormone on body composition and bone metabolism

Endocrine

Prader–Willi syndrome

J. Med. Genet.

Prader–Willi and Angelman syndromes: sister imprinted disorders

Am. J. Med. Genet.

Differential activity of maternally and paternally derived chromosome regions in mice

Nature

Review
Imprinted genes and neuroendocrine function