Researchers identify noncoding RNA crucial for stem cell suppression in the brain.


A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.  The opensource study, published in the journal Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer’s disease, Parkinson’s disease and traumatic brain injury, and in cancer treatment.

The team state that Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.  The name, pronounced ‘Pinky,’ was inspired by the popular American cartoon series Pinky and the Brain.   Pnky is encoded near a gene called ‘Brain,’ and has only been found in the brain so far.

The researchers first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.  These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment.

Using an analytical technique called mass spectrometry the team found that Pnky binds the protein PTBP1, which is also found in brain tumours and is known to be a driver of brain tumour growth. In neural stem cells, Pnky and PTBP1 appear to function together to suppress the production of neurons. The current study found that if one or the other is taken away the stem cells differentiate, making more neurons.  It is also possible that Pnky can regulate brain tumour growth, which means, the team say, that they may have identified a target for the treatment of brain tumours.

The researchers state that the larger significance of the research is that it adds to a growing store of knowledge about lncRNAs, previously unknown sections of the genome that some biologists have referred to as the ‘dark matter’ of the human genome; adding recently, over fifty thousand human lncRNAs have been discovered.

The team surmise that the current data suggest there may be more human lncRNAs than there are genes that code for proteins  It is possible that not all lncRNAs have important biological functions, however, the medical community are making a start toward learning which ones do, and if so, how they function. It’s a new world of experimental biology, and the lab state that they are right there on the frontier.

Source:  UC San Francisco 

While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations.  The Long Noncoding RNA Pnky Regulates Neuronal Differentiation of Embryonic and Postnatal Neural Stem Cells.  Lim et al 2015.

While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations. The Long Noncoding RNA Pnky Regulates Neuronal Differentiation of Embryonic and Postnatal Neural Stem Cells. Lim et al 2015.

2 comments

  • Lisa Vanderburg

    Really enjoy reading your posts Michelle! You are one smart cookie, and need all the learning I can get! But this post….can’t get my head around lncRNAs & PNKYs. I’m an advocate for PD (hubby has it). How would this finding be applicable?

    Like

  • Glad you enjoy the stream. The premise here is the fact that lncRNA named PNKY controls the epigenetic transcription which suppresses neuronal production. And when PNKY is removed neuron production increases fourfold, an enormous amount. Think of epigenetics as the end game in DNA control, messaging and transcription, where the DNA code or ‘program’ manifests to the naked eye by way of a protein, a disease, a cold even, there must have been an epigenetic change to cause these changes. With view to the neuron production, all diseases of the brain cause damage to the surrounding neurons and their connections rolling onto their circuitry, so anything that can cause a production or new neurons and new connection will ultimately fix that circuitry. There is no reason why dopamine producing neurons cannot be produced in the lab using this method.

    Where you are right to question…. How do we stabilise these new neurons where we are unaware of the cause of Parkinson’s? Do we know enough about the disease for these transplanted neurons to also become affected by PD? Will this become a short-term therapy for PD? So will these ‘neuronal injections’ become a regular tune up? Should we couple them with DBS (Deep Brain Stimulation)? That could be a good idea because the next question is, how do we get these regular new neurons into the brain? DBS is shown to work but how safe is it to replenish these neurons on a regular basis? Could we use a reservoir, or a permanently open tube for the transplant into the necessary part of the brain where dopamine is produced in the midbrain. This works for other conditions around the body but an open ‘transplant tunnel’ to the brain? Do we risk infection, as I’m not a trained neurosurgeon I am unsure as to whether this is possible or not so this is pure theory at this point.

    I hope this helps and answers some of your questions.

    Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s