I've discussed the issue of cellular intelligence in a previous series. Nevertheless, new items keep showing up, more or less relevant to the subject. In this case, a new discovery by Hongye Liu1 and Issac S. Kohane offers some interesting points:
Tissue and Process Specific microRNA–mRNA Co-Expression in Mammalian Development and Malignancy
Let me start by blockquoting the abstract:
An association between enrichment and depletion of microRNA (miRNA) binding sites, 3′ UTR length, and mRNA expression has been demonstrated in various developing tissues and tissues from different mature organs; but functional, context-dependent miRNA regulations have yet to be elucidated. Towards that goal, we examined miRNA–mRNA interactions by measuring miRNA and mRNA in the same tissue during development and also in malignant conditions. We identified significant miRNA-mediated biological process categories in developing mouse cerebellum and lung using non-targeted mRNA expression as the negative control. Although miRNAs in general suppress target mRNA messages, many predicted miRNA targets demonstrate a significantly higher level of co-expression than non-target genes in developing cerebellum. This phenomenon is tissue specific since it is not observed in developing lungs. Comparison of mouse cerebellar development and medulloblastoma demonstrates a shared miRNA–mRNA co-expression program for brain-specific neurologic processes such as synaptic transmission and exocytosis, in which miRNA target expression increases with the accumulation of multiple miRNAs in developing cerebellum and decreases with the loss of these miRNAs in brain tumors. These findings demonstrate the context-dependence of miRNA–mRNA co-expression.
Now let's try to see what that means. Among the various types of non-coding RNA (ncRNA) is microRNA. This consists of short strands of RNA, associated with several enzymes, that can work to suppress or, apparently, activate messenger RNA (mRNA) translation.
Before I try to summarize enough about how microRNA works to make my point, let me add another link, for those uncomfortable with Wikipedia, which is sometimes out of date. The Fascinating World of RNA Interference by Afsar Raza Naqvi, Md. Nazrul Islam, Nirupam Roy Choudhury, and Qazi Mohd. Rizwanul Haq. Int J Biol Sci. 2009; 5(2): 97–117. Published online 2009 January 15. It was "Received July 3, 2008; Accepted November 2, 2008", so it's very up-to-date. In fact, it's more up-to-date than the subject of this post in some respects, although the specific discrepancies don't seem to me to affect the conclusions.
MicroRNA is created when DNA is transcribed, by the same mechanism that transcribes mRNA. In fact, the same strand can work as both, as some microRNA is actually contained within introns of the transcription. It works together with a variety of enzymes, guiding them to target mRNA with a complementary sequence. If the match is exact, the mRNA is sliced up and destroyed, while if it's not quite on transcription is repressed in a way that is sometimes reversible (or so it seems).
One thing Liu and Kohane missed is an earlier paper: Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation (free registration required) by Shobha Vasudevan, Yingchun Tong, Joan A. Steitz, which offers the possibility that microRNA can actually enhance translation under some circumstances. (The actual circumstances documented are that there be AU-rich regions near the target sequence on the mRNA and that the cell be in a resting cycle. This may or may not be relevant to the discoveries of Liu and Kohane. It certainly doesn't (IMO) reduce the importance of their discovery.)
Now, what did they discover? They went through a large collection of known microRNA and mRNA and "examined miRNA–mRNA interactions by measuring miRNA and mRNA in the same tissue during development and also in malignant conditions." They "identified significant miRNA-mediated biological process categories in developing mouse cerebellum and lung using non-targeted mRNA expression as the negative control." That is, they identified categories of enzymes whose mRNA was mediated by microRNA by their function within (and between) cells.
They discovered that "[a]lthough miRNAs in general suppress target mRNA messages, many predicted miRNA targets demonstrate a significantly higher level of co-expression than non-target genes in developing cerebellum." This phenomenon appeared to be limited to the cerebellum, at least there was no sign of it in the lung. (We can assume that future research will target various other regions within the brain looking for differences and correlations.)
Now, we know (or rather we appear to know, pending confirmation of Vasudevan et al.), that it's possible for microRNA to up-regulate its targets under some circumstances. It's possible, of course, that it's actually down-regulating some enzyme that can bond to the mRNA at a nearby site and interfere with the microRNA (see Naqvi et al.). There are also probably some other mundane possibilities for what's happening.
But I want to pursue a more interesting speculation: that both microRNA and its target enzymes (mRNA) are being up-regulated by other processes, and that the microRNA is part of a process to "fine-tune" the target expression cell by cell, allowing regulation levels to be kept within very tight bounds. You'll see how this fits with my ideas that much of the gene activation network is analog in nature, depending on precise scalar values for activation rather than just on/off.
So what we're looking at here is the possibility that the mammalian brain uses a subtle and sophisticated system of analog interactions to control the creation rate of specific enzymes during development, and quite possibly during subsequent life of the neuron. We know that signaling molecules can be used for other purposes during development, and in addition, there are developmental process that depend on neurons firing for synchronization and other purposes. It seems likely that the high expression rate of both enzymes and microRNAs that can act to suppress them are associated with these types of developmental features.
One of the mysteries (so far) regarding the development of the vertebrate brain is how, specifically, the neuron knows where to send its axon(s) (a neuron has a single axon, but in many in the brain and CNS the axon splits fairly near the soma (cell body) and the various branches travel to completely different locations). Not only do the axons end up in the right target regions of the brain (or other CNS regions), but they have to end up near the specific cells in the target regions that need their input. In the case of many brain regions in human fetuses and infants, the target regions may consist of several square centimeters (or more) of cortical area. Most incoming neurons only innervate a tiny fraction of this cortical area, and they need a way to know "where they are" in order to figure out "where to go".
For example, the receptors that are used for identifying odors in mature olfactory sensory neurons are also involved in guiding developing axons to their targets in the olfactory bulb. (See Odorant Receptor–Derived cAMP Signals Direct Axonal Targeting (requires free registration) by Takeshi Imai, Misao Suzuki, and Hitoshi Sakano, also Odorant receptors at the growth cone are coupled to localized cAMP and Ca2+ increases by Micol Maritana, Giovanni Monacoa, Ilaria Zamparoa, Manuela Zaccolob, Tullio Pozzana and, Claudia Lodovichi)
Another example is that in many mammals the neurons of the retinal create "retinal waves" based on their location before birth or the opening of the eyes (depending on species). (See Retinal Waves Trigger Spindle Bursts in the Neonatal Rat Visual Cortex by Ileana L. Hanganu, Yehezkel Ben-Ari, and Rustem Khazipov.) This has been proposed to be partly responsible for the response by each neuron in the primary visual area to specific combination(s) of orientation, motion direction, and velocity. Neurons in the immature retinogeniculate synapse behave differently than at maturity. (See Different Roles for AMPA and NMDA Receptors in Transmission at the Immature Retinogeniculate Synapse by Xiaojin Liu and Chinfei Chen.) This is also occurring during a period of rapid development and ongoing establishment and remodeling of neural interconnections.
It's been questioned in Establishment of a Scaffold for Orientation Maps in Primary Visual Cortex of Higher Mammals by Agnieszka Grabska-Barwinska and Christoph von der Malsburg whether "retinal waves" could be directly responsible for providing the course-scale pattern for this process due to timing:
The existence of the postulated coarse-scale activity patterns remains to be verified. Retinal waves could be one source of patterns on the proper scale, but these patterns disappear before OMs are visible in optical recording. It is possible that orientation selectivity is encoded in long-range horizontal connections before the visual system matures to the level allowing OM detection. Alternatively, other possible sources of large-scale patterns exist (see Materials and Methods, Evaluation of assumptions).
It seems a likely speculation that both these process involve the simultaneously up-regulated microRNAs and mRNAs, probably (IMO) to allow fine-tuning of location data, and perhaps "remembering" it in the case of the retinal waves.
Another possible application is for localization. The axon, and even the major dendrites of pyramidal (and a few other types of) cells in the brain are far enough from the soma to provide a major cost savings in shipping the mRNA out to the end before using it to build enzymes, rather than building them in the soma and shipping the much higher volumes of finished enzymes out to where they're needed. It seems plausible (and certainly worth researching) that the translation of some or most of these enzymes' mRNAs is localized far from the soma, and that the microRNAs discussed in this paper are involved in that process.
Altogether, this paper confirms the already growing awareness that microRNAs are involved in many previously unknown complex processes, many of them potentially analog, and intensifies the need for plenty of research regarding what and how.
Liu, H., & Kohane, I. (2009). Tissue and Process Specific microRNA–mRNA Co-Expression in Mammalian Development and Malignancy PLoS ONE, 4 (5) DOI: 10.1371/journal.pone.0005436
Links: (Many of these aren't called out in the text, but they represent further detail regarding the subject here, and may be useful for anybody wanting to dig further.)
Arabidopsis ARGONAUTE1 is an RNA Slicer that selectively recruits microRNAs and short interfering RNAs
Argonaute2, a Link Between Genetic and Biochemical Analyses of RNAi (requires free registration)
Production and actions of small RNAs
Piwi-interacting RNAs and the role of RNA interference
Specificity of microRNA target selection in translational repression
Asymmetry in the Assembly of the RNAi Enzyme Complex
MicroRNAs: Genomics, Review Biogenesis, Mechanism, and Function
MicroRNAs in Gene Regulation: When the Smallest Governs It All
The Fascinating World of RNA Interference
Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation (requires free registration)
Odorant Receptor–Derived cAMP Signals Direct Axonal Targeting (requires free registration)
Odorant receptors at the growth cone are coupled to localized cAMP and Ca2+ increases
Retinal Waves Trigger Spindle Bursts in the Neonatal Rat Visual Cortex
Different Roles for AMPA and NMDA Receptors in Transmission at the Immature Retinogeniculate Synapse
Establishment of a Scaffold for Orientation Maps in Primary Visual Cortex of Higher Mammals
Synchrony between orientation-selective neurons is modulated during adaptation-induced plasticity in cat visual cortex
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