Posts tagged epigenetics

Neurobiologists at the Friedrich Miescher Institute for Biomedical Research (FMI) are the first to show that directional migration of neurons during brain development is controlled through epigenetic processes. In an elaborate study bridging epigenetics and neurobiology, the scientists found that the migratory pattern is orchestrated through epigenetic regulation of genes within neurons and spatial signals in the environment. Their study has been published in Science.

As the foundation for our mind is laid, 100 billion cells are formed and appropriately connected in the brain. Despite the huge number of cells, no aspect of this process is left entirely to chance. Neurons divide, take on defined identities, migrate to the correct nodes in the network and send out their connecting axons along predefined paths to make contact with specific target neurons. The blueprint for these arrangements is encoded in the genome. However, how coordinated transcription of genes is finely tuned to achieve the precision of these processes is not yet clear.

A study by the research group of Filippo Rijli, group leader at the FMI and Professor of Neurobiology at the University of Basel, shows now for the first time that long-distance neuronal migration in the developing brain is regulated through transcriptional programs that are epigenetically controlled.

In their study published in Science, the neurobiologists have looked at a part of the brain called the brain stem and, in particular, at the neuronal ensembles forming the so-called precerebellar pontine nuclei. These nuclei are particularly important for the relay of information from the sensory and motor cortex to the cerebellum. During development, neurons, which will gather to form the pontine nuclei, migrate a long way from a distant progenitor compartment to their final positions, where they form connections that are vital for coordinated movement. The migratory path of these cells is defined by the relative position of the neuron in the progenitor compartment and is controlled by its specific combinatorial expression of Hox genes. Hox genes encode transcription factors and play an important role in many developmental processes that rely on a body plan and confer cellular identity.

It has been known that neurons in the precerebellar pontine nuclei start to migrate in the wrong direction as soon as their Hox identity has been disrupted. The Rijli team has now shown that epigenetic processes control the maintenance of appropriate Hox expression during migration. The key player in this scenario is a major contributor to mammalian epigenetic control, the histone methyl-transferase Ezh2. Ezh2 methylates histones and silences specific stretches of DNA, thus maintaining certain Hox genes repressed, while allowing expression of others.

Ezh2 also regulates the appropriate response to environmental clues that direct neuronal migration. The cells in the brain stem bathe in a sea of attractants and repellants. They respond to these stimuli depending on their identity and adapt their migratory paths. Rijli and colleagues found that Ezh2 controls transcription of both environmental Netrin, a neuronal attractant molecule and of its repellant receptor Unc5b in migrating neurons, such that the appropriate balance between attraction and repulsion is maintained throughout migration to keep neurons on track.

“Being able to link epigenetic regulation with a complex process such as long-distance directional neuronal migration during brain development is extremely exciting,” comments Rijli. “All the more we were delighted to see that the migratory pattern is not only epigenetically maintained through an intrinsic program established in the progenitor, but is also coordinated with an Ezh2-dependent silencing program that regulates the spatial distribution of extrinsic signals in the migratory environment. The knowledge gained from our studies contributes as well to our understanding of certain neurological syndromes that are caused by faulty neuronal migration and are currently incurable.”

(Source: fmi.ch)

Research from the Perelman School of Medicine at the University of Pennsylvania and Massachusetts General Hospital (MGH) reveals that sons of male rats exposed to cocaine are resistant to the rewarding effects of the drug, suggesting that cocaine-induced changes in physiology are passed down from father to son. The findings are published in the latest edition of Nature Neuroscience.

"We know that genetic factors contribute significantly to the risk of cocaine abuse, but the potential role of epigenetic influences – how the expression of certain genes related to addiction is controlled – is still relatively unknown," said senior author R. Christopher Pierce, PhD, associate professor of Neuroscience in Psychiatry at Penn. "This study is the first to show that the chemical effects of cocaine use can be passed down to future generations to cause a resistance to addictive behavior, indicating that paternal exposure to toxins such as cocaine can have profound effects on gene expression and behavior in their offspring."

In the current study, the team used an animal model to study inherited effects of cocaine abuse. Male rats self-administered cocaine for 60 days, while controls were administered saline. The male rats were mated with females that had never been exposed to the drug. To eliminate any influence that the males’ behavior would have on the pregnant females, they were separated directly after they mated.

The rats’ offspring were monitored to see whether they would begin to self-administer cocaine when it was offered to them. The researchers discovered that male offspring of rats exposed to the drug, but not the female offspring, acquired cocaine self-administration more slowly and had decreased levels of cocaine intake relative to controls. Moreover, control animals were willing to work significantly harder for a single cocaine dose than the offspring of cocaine-addicted rats, suggesting that the rewarding effect of cocaine was decreased.

In collaboration with Ghazaleh Sadri-Vakili, MS, PhD, from MGH, the researchers subsequently examined the animals’ brains and found that male offspring of the cocaine-addicted rats had increased levels of a protein in the prefrontal cortex called brain-derived neurotrophic factor (BDNF), which is known to blunt the behavioral effects of cocaine.

"We were quite surprised that the male offspring of sires that used cocaine didn’t like cocaine as much," said Pierce. "While we identified one change in the brain that appears to underlie this cocaine resistance effect, there are undoubtedly other physiological changes as well and we are currently performing more broad experiments to identify them. We also are eager to perform similar studies with more widely used drugs of abuse such as nicotine and alcohol."

The findings suggest that cocaine use causes epigenetic changes in sperm, thereby reprogramming the information transmitted between generations. The researchers don’t know exactly why only the male offspring received the cocaine-resistant trait from their fathers, but speculate that sex hormones such as testosterone, estrogen and/or progesterone may play a role.

(Source: eurekalert.org)