Control of fertility: A new player identified

May 2, 2016, Institut National de la Sante et de la Recherche Medicale

Individual small RNAs are responsible for controlling the expression of gonadoliberin or GnRH (Gonadotropin-Releasing Hormone), a neurohormone that controls sexual maturation, the appearance of puberty, and fertility in adults. This has just been demonstrated by the "Development and Plasticity of the Neuroendocrine Brain" team led by Vincent Prévot, Inserm Research Director (Jean-Pierre Aubert Research Centre, Lille). The involvement of microRNAs, transcribed from DNA, occurs around birth, and marks a key step in postnatal development. Failure of these microRNAs to act leads to the disruption or even total cessation of GnRH production by the hypothalamic neurons that synthesise it, and hence to infertility. In the most serious cases, sterility may result. Details of this work in mice are published in the 2 May 2016 issue of the journal Nature Neuroscience.

Reproductive function is determined by events that take place in the brain. Gametogenesis (the production of spermatozoa and oocytes) and the secretion of hormones by the ovaries and testes are heavily dependent on the hypophysis, a small gland located below the brain, to which it is connected by a capillary network. The latter is in turn controlled by a glandular "orchestra conductor" located at the base of the brain, the hypothalamus. During postnatal development, activation of a small number of highly specialised neurons (the GnRH neurons) in the hypothalamus leads to the synthesis of a hormone, gonadoliberin or GnRH (Gonadotropin Releasing Hormone), and this process leads to the appearance of puberty.

This step, known as "mini-puberty" constitutes the first activation of the reproductive axis by the brain. It occurs between the first and third months of life of the infant, and is important to the correct course of sexual maturation. At puberty, GnRH stimulates the synthesis by the hypophysis of other hormones, which in turn enter the bloodstream to promote the growth of the gonads (ovaries and testes), and to subsequently ensure reproductive function.

The appearance of puberty remains one of the greatest scientific enigmas of the 21st century. In the last 30 years, the discovery of mutations in various parts of the genome in patients with disorders of puberty has made it possible to identify some genes involved in this process.

However, physicians and scientists believe that these genes are responsible for only a third of the disorders of puberty encountered in patients. The discovery of the involvement of microRNAs opens up considerable prospects for the medical management of these patients, from both a diagnostic and therapeutic point of view.

MicroRNAs are small non-coding RNAs transcribed from our DNA. In contrast to messenger RNAs (mRNA), they are not translated into proteins. Because of this, microRNAs are not part of the "coding genome," but constitute what some people call the epigenome. Regulation of gene expression, e.g. expression of the GnRH gene, by microRNAs is therefore considered "epigenetic" regulation.

Research conducted in mice by Vincent Prévot's team shows that birth induces a radical change in the expression of microRNAs in the hypothalamic GnRH neurons. This modification of the microRNA expression profile is essential to the inhibition of the expression of transcription factors (proteins that activate or inhibit gene expression) that have a repressive effect on GnRH expression. This inhibition of inhibitory factors allows increased production of GnRH, which is indispensable to infantile and juvenile sexual maturation, and the occurrence of puberty. Indeed, in the absence of microRNAs, the expression of transcription factors that inhibit GnRH increases, and leads to the extinction of GnRH synthesis in the brain, leading to the arrest of , absence of puberty, and complete sterility in adult individuals. Analysis of the GnRH gene in humans shows that analogous phenomena might occur in our own species. The mechanism elucidated by this team might therefore explain the absence of and the occurrence of infertility in some patients for whom no mutation or polymorphism (variation in DNA sequence) has been identified in the coding genome.

In terms of diagnosis, the study carried out by Vincent Prévot's team in Lille shows the interest of analysing DNA segments from which microRNAs are transcribed, as well as the genome segments that encode their binding sites on the target genes. "The work published today shows the importance of studying the genome sequences that will be transcribed into mRNA molecules, to which microRNAs bind in order to regulate their translation into protein," add the researchers.

From a therapeutic standpoint, the interaction of microRNAs with the genes they regulate may be prevented or mimicked by the administration of small analogous molecules, for which the study done by Vincent Prévot's team provides proof of concept.

Explore further: Faulty gene can delay or block puberty

More information: A microRNA switch regulates the rise in hypothalamic GnRH production before puberty, Nature Neuroscience, DOI: 10.1038/nn.4298

Related Stories

Faulty gene can delay or block puberty

March 26, 2014
More than 4% of adolescents suffer from early or late-onset puberty, which is associated with health problems including obesity, type-2 diabetes, heart disease and cancer. The findings of the study will make diagnosis easier ...

Optogenetic research shows which neurons flip fertility master switch

October 5, 2015
New Zealand scientists have achieved another milestone in their world-leading efforts to understand the neural mechanisms underlying the brain's master control of fertility.

Researchers elucidate network of genes that control when puberty begins

December 16, 2015
In expanding our knowledge of how the brain controls the process of sexual development, researchers at Oregon Healthy & Science University and the University of Pittsburgh have identified for the first time members of an ...

Neuroscientists reveal mechanism crucial to molding male brains

November 11, 2014
University of Otago researchers have discovered that neural circuitry they previously showed was vital to triggering ovulation and maintaining fertility also plays a key role in moulding the male brain.

Recommended for you

New neurons in the adult brain are involved in sensory learning

February 23, 2018
Although we have known for several years that the adult brain can produce new neurons, many questions about the properties conferred by these adult-born neurons were left unanswered. What advantages could they offer that ...

Study in mice suggests personalized stem cell treatment may offer relief for multiple sclerosis

February 22, 2018
Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis ...

Nolan film 'Memento' reveals how the brain remembers and interprets events from clues

February 22, 2018
Key repeating moments in the film give viewers the information they need to understand the storyline. The scenes cause identical reactions in the viewer's brain. The results deepen our understanding of how the brain functions, ...

Biomarker, clues to possible therapy found in novel childhood neurogenetic disease

February 22, 2018
Researchers studying a rare genetic disorder that causes severe, progressive neurological problems in childhood have discovered insights into biological mechanisms that drive the disease, along with early clues that an amino ...

A look at the space between mouse brain cells

February 22, 2018
Between the brain's neurons and glial cells is a critical but understudied structure that's been called neuroscience's final frontier: the extracellular space. With a new imaging paradigm, scientists can now see into and ...

Schizophrenia a side effect of human development

February 21, 2018
Schizophrenia may have evolved as an "unwanted side effect" of the development of the complex human brain, a new study has found.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.