“If we knew what we were doing it would not be called research, would it?” – Albert Einstein
The article for today’s post starts out this way, “ Nerve cell structures in the adult hippocampus are sustained by factors whose identities have remained largely mysterious so far.”
“Researchers now report that a protein that has primarily been studied for its role in early animal development also plays a surprising role in maintaining the structure of hippocampal neurons in adult mice.”
The article’s words seem to be a clue that something extraordinary may be going on beneath the surface, but they too only skim on the surface, gliding on what is easily said but not caring to look much further than what’s in front of their eyes.
“The finding that embryonic deletion of Wnt5a in neurons did not elicit any structural abnormalities in CA1 pyramidal neurons during development suggests that neuronal Wnt5a is dispensable for the establishment or maturation of hippocampal connectivity in vivo.
“Notably, we demonstrate that Wnt5a, derived from CA1 pyramidal neurons themselves, is critical for sustaining dendritic architecture in the adult hippocampus, implying that specificity for neuronal wiring is intrinsic to active neurons themselves in hippocampal circuits.”
Hmmm….not very illuminating, though, is it? What, in the scheme of things, might this mean. But really more than for the sake of the alternately bewildered and bored reader, for the sake of the researchers and the neuroscience game itself, how can they simply skin the surface with their research without seeking some sort of underlying paradigm to guide their thinking, guide their investigating, and, for God’s sake, to guide their writing.
One of the difficulties of posting these kinds of articles is that the media paparazzi headlines seem to announce some wondrous or provocative breakthrough. The actual paparazzi story has almost no useful detail..as if readers cannot assimilate or digest any medical or technical vocabulary. But lastly the researchers themselves, as in this study, really only focus on the narrowest interpretation of their findings, and to call what they provide an interpretation would quite a euphemism.
Now we believe this set of molecules (see below) is crucial for a heckuva lot more than the researchers state. We will have to expand and clarify the significance of this post soon. For the moment it is noteworthy that the entire research article itself nowhere actually approaches the significance of these findings…or at least what can be seen with some further examination and which we hope to provide shortly.
This question of “asymmetrical division” is perhaps one of the most significant in our understanding of all life. An asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to symmetric cell divisions which give rise to daughter cells of equivalent fates.
Asymmetrical division occurs when a cell divides in such a manner as to produce two very different kinds of cells, not just splitting itself and symmetrical produced ‘two of its kind”. In this kind of division…which started somewhere and somehow…the cell gives rise to one cell which indeed is of its kind and destined to “take its place” as it were, but the other cell is a new type of cell with altered genomic expression
A hallmark of all stem cells is the ability to simultaneously generate identical copies of themselves but also to give rise to more differentiated progeny. Stem cells self-renew but also give rise to daughter cells that are committed to lineage-specific differentiation. To achieve this remarkable task, they can undergo an intrinsically asymmetric cell division whereby they segregate cell fate determinants into only one of the two daughter cells. Alternatively, they can orient their division plane so that only one of the two daughter cells maintains contact with the niche and stem cell identity.
- Symmetric cell division of stem cells ensures that a constant pool of stem cells is available by giving rise to two identical daughter cells both endowed with stem cell properties.
- However, asymmetric division of stem cells results in the production of only one stem cell and a progenitor cell with limited self-renewal potential.
- Progenitor cells that are produced via asymmetric cell division will go through additional rounds of cell division until they are terminally differentiated into a mature, specialized cell…or they experience apoptosis as their destiny in the course of this altered fate.
- Asymmetric division can be controlled by both intrinsic and extrinsic factors.
- Intrinsic factors involve differing amounts of cell-fate determinants being distributed into each daughter cell, while extrinsic factors involve interactions with neighboring cells and the micro and macro environment of the precursor cell and, of course, this is where the various actions of WNT signaling come in.
The stem cell is in close contact with the stem cell niche and depends on this contact for maintaining the potential to self-renew . By orienting its mitotic spindle perpendicularly to the niche surface, it ensures that only one daughter cell can maintain contact with the stem cell niche and retain the ability to self-renew.
Mechanisms of Asymmetric Stem Cell Division http://www.cell.com/cell/fulltext/S0092-8674(08)00208-0
In contrast to intrinsically asymmetric cell divisions, which usually follow a predefined developmental program, niche-controlled stem cell divisions offer a high degree of flexibility. Occasionally, the stem cell can divide parallel to the niche, thereby generating two stem cells to increase stem cell number or to compensate for occasional stem cell loss. For this reason, niche mechanisms are more common in adult stem cells, whereas intrinsically asymmetric divisions predominate during development.
Cell–cell adhesion protein E-cadherin functions as an instructive cue for cell division orientation. This is mediated by the evolutionarily conserved factors to which WNT has a very profound relation and which regulates cortical attachments of astral spindle microtubules. E-cadherin is linked to the actin cytoskeleton through bound catenin proteins (α-, β- and p120-catenin), and forms a signalling platform that triggers intracellular responses. Importantly, loss of E-cadherin disrupts not only cell–cell adhesion but also the orientation of cell divisions,
Cell division orientation is coupled to cell–cell adhesion by the E-cadherin/LGN complex http://www.nature.com/articles/ncomms13996
What is key though is how and why and when the cell might tend to asymmetric division or not? The most globally interesting aspect of this WNT molecule’s function in the brain and elsewhere through many species turns out to be that it regulates just when and how various cells, either in the embryonic state or later in adult life, “know” when to asymmetrically divide or not.
The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals into a cell through cell surface receptors. Wnt signaling was first identified for its role in carcinogenesis, then for its function in embryonic development.. The embryonic processes it controls include body axis patterning, cell fatee specification, cell proliferation and cell migrations. These all seem to be distinct word=labels, but if we look, we can see that they are all interconnected and indeed sum up to pretty much everything than counts in both embryogenesis and, in the brain, in neurogenesis.. These processes are necessary for proper formation of important tissues including bone, heart and muscle.
The canonical Wnt pathway leads to regulation of gene transcription. The noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell. The noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
The conserved Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-β, and BMP, within different cell types and tissues.
The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family.
. Without Wnt signaling, . In the absence of Wnt-signal (Off-state), β-catenin, an integral E-cadherin cell-cell adhesion adaptor protein and transcriptional co-regulator, would not accumulate in the cytoplasm i but would be targeted by coordinated phosphorylation since a destruction complex that would normally degrade it via its ubiquitination and proteasomal degradation,.
In the presence of Wnt ligand (On-state), the co-receptor LRP5/6 is brought in complex with Wnt-bound Frizzled.
Stablized β-catenin is translocated to the nucleus via Rac1 and other factors, where it binds to LEF/TCF transcription factors, displacing co-repressors and recruiting additional co-activators to Wnt target genes.
Additionally, β-catenin cooperates with several other transcription factors to regulate specific targets. Importantly, researchers have found β-catenin point mutations in human tumors that prevent GSK-3β phosphorylation and thus lead to its aberrant accumulation.
Interactions between Wnt signaling pathways also regulate Wnt signaling. The Wnt/calcium pathway, for example, can inhibit TCF/β-catenin, preventing canonical Wnt pathway signaling. ProstaglandinE2 is an essential activator of the canonical Wnt signaling pathway. Interaction of PGE2 with its receptors E2/E4 stabilizes beta catenin through cAMP/PKA mediated phosphorylation. The synthesis of PGE2 is be necessary for Wnt signaling mediated processes such as tissue regeneration and control of stem cell population in zebrafish and mouse
Here is an instructive video on CADHERINS:
Interplay of Cadherin-Mediated Cell Adhesion and Canonical Wnt Signaling https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828280/
Through the Wnt pathway, signals are exchanged between neighboring cells and tissues: Wnt proteins that are secreted from one type of cell interact with surface receptors of neighboring cells. There the signals are passed through the cytoplasm to the nucleus, where gene regulation is modulated. This process controls proliferation, survival, cell migration, differentiation, and patterning in the receiving cells and tissues.”
The process for formation of new cells which go on to be part of ongoing organs or tissues requires this kind of division. And the mechanisms which regulate whether the embryo matures adequately to sustain life in its environment or whether the stem cells will provide the organism with new cells, whether neurons or other specialized mature cells are dependent on such factors as WNT molecules. Indeed the WNT molecule is an ancient evolutionarily conserved molecule that is no doubt very interesting in many ways
For those seeking a discussion of just how much the WNT signaling means. we can see how this further level of knowledge is being studied in heart disease:
“Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607163/
For new, we hope that we have indicated what might hide down deeper behind the tip of this iceberg, which goes unmentioned here. Most importantly we should note the organisms are evolved “intelligently” even if not always to be very intelligent themselves.
This means that molecules such as WNT will act very differently on the cells and their structuring and development depending on whether they are in the embryonic stage, or when they are in the post natal stage where the organism is bequeathed its endowment of stem cells, or after the stem cells are released and allowed to mature and asymmetrically divide into progenitors, and when the cells are finally matured and interactive with each other in the adult form.
Wnt signaling induces differentiation of pluripotent stem cells into mesoderm and endoderm progenitor cells In order to have the mass differentiation of cells needed to form the specified cell tissues of different organisms, proliferation and growth of embryonic stem cells must take place. This process is mediated through canonical Wnt signaling, which increases nuclear and cytoplasmic β-catenin. Increased β-catenin can initiate transcriptional activation of proteins such as cyclin D1 which control the G1 to S phases transition in the cell cycle
Entry into the S phase causes DNA replication and ultimately mitosis, which are responsible for cell proliferation.[ his proliferation increase is directly paired or related to varying extents in varying different situations with cell differentiation because as the stem cells proliferate, they also differentiate.
These progenitor cells further differentiate into cell types such as endothelial, cardiac and vascular smooth muscle lineages Wnt signaling induces blood formation from stem cells. This allows for overall growth and development of specific tissue systems during embryonic development. This is apparent in systems such as the circulatory system where Wnt3a leads to proliferation and expansion of hematopoietic stem cells needed for red blood cell formation. Wnt1 antagonizes neural differentiation and is a major factor in self-renewal of neural stem cells. This allows for regeneration of nervous system cells, which is further evidence of a role in promoting neural stem cell proliferation.
Interestingly..or should we say fascinatingly…these cells and the manner in which WNT functions go a long way to provide a full circle feedback to the those cells in the niches which still await future possible future development. Various factors at each time in life will determine just what sort of a balance there is in this ‘asymmetry”, that is, whether more cells are simply reproduced and the number increases, or whether a greater proportion go on into differentiation and maturity.
This is likely somehow the manner in which single cells organisms back in evolutionary time managed to evolve to become multicellular organisms and how those organisms managed to evolve in creatures with different “tissues’ and ‘organs” and the radical and dazzling spectrum of phenotypes we see on our planet.
This manner in which cells within our tissues can communicate and coordinate as a result of their overall patterns and interactions of communications between these three major forms of “junctions’.s the key to much of life…and much of disease. The proportions and timing of whether differentiation or increase in number preponderates. We hope that you excuse us for taking such a digression in order to point out what these researchers have stumbled across here.
The gap junction as a “Biological Rosetta Stone”: implications of evolution, stem cells to homeostatic regulation of health and disease in the Barker hypothesis http://link.springer.com/article/10.1007%2Fs12079-010-0108-9
The author tells us:
“The discovery of the gap junction structure, its functions and the family of the “connexin” genes, has been basically ignored by the major biological disciplines. These connexin genes code for proteins that organize to form membrane-associated hemi-channels, “connexons”, co-join with the connexons of neighboring cells to form gap junctions.
Gap junctions appeared in the early evolution of the metazoan. Their fundamental functions, (e.g., to synchronize electrotonic and metabolic functions of societies of cells, and to regulate cell proliferation, cell differentiation, and apoptosis), were accomplished via integrating the extra-cellular triggering of intra-cellular signaling, and therefore, regulating gene expression.
These functions have been documented by genetic mutations of the connexin genes and by chemical modulation of gap junctions
Specifically, the modulation of gap junctional intercellular communication (GJIC), either by increasing or decreasing its functions by non-mutagenic chemicals or by oncogenes or tumor suppressor genes in normal or “initiated” stem cells and their progenitor cells, can have a major impact on tumor promotion or cancer chemoprevention and chemotherapy.
Here is a glimpse into this extraordinary review article
“When the evolutionary moment occurred to provide a group of cells to adhere, possibly because of the ability of organisms to synthesize collagen in an oxygenated environment ( and act as a single multi-cellular individual, new phenotypes of
(a) growth control,
(b) differential expression or differentiation of the total genome,
(c) selective suicide or apoptosis of individual cells ;
(d) the appearance of a niche for harboring unique cells, namely germ-line and somatic/adult stem cells appeared.
These stem cells helped the survival of the species, as well as providing the means to grow, to repair wounds.
The trade-off of the ability of stem cells to symmetrically and asymmetrically divide was “mortality” or senescence of both somatic cells and the individual. This gave the metazoan alternative means, besides symmetric cell division, to be an adaptive strategy to survive an ever-changing environment.
This transition included the ability of some metazoan cells to divide either via symmetric cell division (to make two daughter cells that were phenotypically-alike) or asymmetrically (to have one daughter to be as its mother, while the other could differentiate).
The ability of the metazoans to generate muscle cells, nerve cells, hepatocytes, keratinoctyes and retinal cells gave the metazoans a unique means to adapt to their environments.
By the same token, they had to create a special “niche” that allowed to the stem (both germ-line and somatic) cells to be sequestered from those factors that allowed the other somatic, non-stem cells to differentiate. “
We shall have much more to say in our expansion of this post in order to include astrocytes and microglia, As you might expect these cells and the structures and networks that they form among themselves are actually the key and the guide to how these WNT molecules managed to be able to participate in the signaling and determination of the nature and extent and timing of the asymmetrical division which characterizes all life. In fact it is the WNT receptors on these cells and their signaling in turn via the WNT family that is behind what is seen here in the current research.
Here is a truly informative link on the manner in which WNT and the Astrocytes work together to achieve the results that these researchers witnessed.—- and which they will never explain by only looking at the neurons.
OK..so, let us go back to the paparazzi and then a few more words from the researchers…which, truly, don’t even hint of all this glorious stuff going on behind the scenes.
But, just one more thing…and if any of our readers are interested we can provide a further glimpse into this amazing fact. We all have likely heard of the “golden mean” and the Fibonacci series of numbers which converge to that ratio, and not only did worship of numbers start way back with Greeks when they realize how much in nature approximated this ration, but so much of organic life seems to manifest this ration and the Fibonacci sequence of numbers.
However this “golden mean’ as it approaches something in the are of “1.6” and the manner in which the Fibonacci sequence is itself generated are very much a reflection of the underlying driving force behind the emergence of life and of its evolution via ‘asymmetrical division” and this kind of “asymmetry” ongoing almost everywhere and every time in every creature big and small is not a sign of a divine intervention…but simply what happens down the road when “asymmetrical division” is allowed to progress.. A whole new world out there emerges…:)
To us, admittedly not privy to the inner sancta of neuroscience, to us this patterning and the detailed examination of the signaling between adjacent cells in contact with each other than either enhances or diminishes their tendency to either symmetrically or asymmetrically divide seems to eerily remind of us Alan Turing’s last great (and still unrecognized work) in which he used the “reaction diffusion equation” forms of mathematical expression to capture the essence of embryonic development.
The Chemical Basis of Morphogenesis,” was published in 1952 provided a model is that could explain pattern formation without a preformed pattern. That is, the reaction-diffusion model can explain how those initial patterns form in the first place. While fly development begins with a maternal injection of bicoid into the oocyte, a reaction-diffusion system can theoretically give rise to a pattern without an initial asymmetry.
“Alan Turing’s Reaction-Diffusion Model – Simplification of the Complex” https://phylogenous.wordpress.com/2010/12/01/alan-turings-reaction-diffusion-model-simplification-of-the-complex/
While the Turing model could mimic the embryonic patterns of flies, the model had no biological basis. This discrepancy between model and reality caused the reaction-diffusion system (and other mathematical models) to fall from favor in the biology community.
“…Many theoreticians sought to explain how periodic patterns could be organized across entire large structures. While the math and models are beautiful, none of this theory has been borne out by the discoveries of the last twenty years. The mathematicians never envisioned that modular genetic switches held the key to pattern formation, or that the periodic patterns we see are actually the composition of numerous individual elements” . In other words, mathematically elegant but biologically irrelevant.”
Needless to say we have a lot more faith in the genius of Turing to be able to intuit the key underlying mathematical modeling of embryogenesis than the genetic determinist acolytes of the past fifty years and their simplistic gene models that now show themselves to be primitive, indeed. “Pure mathematics,” said Einstein, is, in its way, the poetry of logical ideas.” And that is surely what Turing was, a poet decades ahead of his time, in capturing the mathematical form of this asymmetric division harmony of nature.
As to how it is the astrocytes and microglia actually provide an incredible network and scaffolding for the neurons to seem to doing “their own thing” is an equally amazing story…that reflects what happens to all cells in all areas of organic life.
We cannot do justice this radically new insight into how astrocytes really work, and, even though we thought they were important, how much more important they are in neuronal function than even we though.
If you care to explore this article you will see how the riddle of consciousness itself may be phrased in a more answerable way when we stop fooling around with the mundane “wiring’ or neuronal networks and appreciate the higher level of networking achieved by the Astrocytes..that is behind the neuronal events:
To arouse your curiosity, we quote the authors, ‘the active astroglial network functions as a “Master Hub” that integrates results of distributed processing from several brain areas and supports conscious states. Response of this network would define the effect exerted on neuronal plasticity (membrane potentiation or depression), behavior and psychosomatic processes.”
Astrocytes and human cognition: Modeling information integration and modulation of neuronal activity
Cells have a habit of actually tending to cluster and connect to each other in stunning ways. This is very much what we see in bacteria and biofilm formation, but we also see the very same process in the various tissues and organs of our human bodies, and, yes, this networking, this contact and connection between the millions and millions of astrocytes (those star shaped cells) in a lattice work that has never been seen or even considered till recently also depends on these same WNT molecules…and once that structure is in place and “doing its’ thing’ then the rather simple and unimpressive neurons can seem to be the “stars of the show’….but behind the scenes this is how the WNT molecules help determine what happens to those neurons…and the astrocytes and microglia are the doing the ‘heavy lifting’.
OK, now we will get back to what our boring medical paparazzi press release says, hopefully, now we can perhaps see the “rest of the story” and do some reading between the lines… 🙂
“These findings suggest that the protein plays an important role in maintaining dendrite structures as the mouse ages.
“The team went further by showing that when the Wnt5a protein was reintroduced after the dendrites had started to deteriorate in aged mice, the nerve cell structures were restored – to a degree the scientists did not expect.”
The researchers themselves say little more, http://www.pnas.org/content/early/2017/01/03/1615792114
“Here, using tissue-specific deletion in mice, we reveal Wnt5a, a member of the Wnt family of developmental morphogens, as an essential factor for the long-term stability of dendritic architecture in the adult hippocampus.
“”Wnt5a influences synaptic plasticity and related cognitive functions in the mature hippocampus through CaMKII-mediated signaling, Rac1-dependent actin dynamics, and cyclic AMP-responsive element binding-mediated NMDA receptor biosynthesis.
In the long-term, Wnt5a-mediated regulation of cytoskeletal signaling and excitatory synaptic transmission is responsible for the maintenance of dendritic arbors and spines in adult CA1 pyramidal neurons. These findings provide insight into the poorly understood structural maintenance mechanisms that exist in the adult brain.”
OK…so what have they told us, really? Not very much….just the most superifical aspects of what we have seen going on in our brains with today incredible technology.
Wnts are evolutionarily conserved signaling molecules that have been classically associated with embryonic patterning and establishment of neural circuits . That these classic developmental cues may have critical functions in the adult brain has been implied by recent findings that broad-spectrum blockade or activation of Wnt pathway components affects synaptic structure, plasticity, and cognitive functions in adult animals
However, surprisingly little is known about which of the 19 vertebrate Wnts is essential for adult nervous system functions in vivo.
Here, we show that deletion of a single Wnt family member, Wnt5a, is sufficient to elicit profound disruptions in synaptic plasticity, structural maintenance, and learning and memory in adult mice, identifying the importance of this particular non-canonical Wnt in later-life functions. Thus, the loss of Wnt5a cannot be compensated for by other Wnts in the adult hippocampus
In the long-term, Wnt5a-mediated regulation of cytoskeletal signaling and excitatory synaptic trans- mission is responsible for the maintenance of dendritic arbors and spines.
The finding that embryonic deletion of Wnt5a in neurons did not elicit any structural abnormalities in CA1 pyramidal neurons during development suggests that neuronal Wnt5a is dispensable for the establishment or maturation of hippocampal connectivity in vivo.
These results were surprising in the context of reported developmental functions for Wnt5a in cultured hippocampal neurons, and in embryonic processes in other brain regions . In hippocampal neurons, several signaling pathways have been shown to influence dendrite morphogenesis, maturation, and stability in vitro and in vivo “
(more to come – we were just having some fun here sketching out the future )