Basal ganglia subcircuits distinctively encode the parsing and concatenation of action sequences.
Jin et al. Nature Neuroscience, Jan 2014.

When we learn to play a musical instrument – say the guitar – first, we have to learn notes, scales and chords; only then we will be able to play a song. The very same rule applies to our basic functions. For example, when we learn how to read, we first learn the alphabet and the rules of grammar, and then we start making sense of sentences. Neuroscientists have been intrigued by this process for many years and they have wanted to understand how our brains efficiently perform complex cognitive functions by connecting separate elements to produce a unique meaningful sequence. A recent study shed some light on this very important question. Scientists found that a specific area of the brain, the basal ganglia, can signal the integration of individual elements into a behavioral sequence. Scientists designed an experiment where they first trained mice to perform gradually faster sequences of lever presses. This behavioral test is very similar to a person learning to play a guitar solo at an increasingly faster pace. Then, they recorded the neural activity in the basal ganglia of mice performing the task and discovered that basal ganglia neurons treat a whole sequence of actions as a single behavior. This mechanism is called “chunking,” which allows the brain to efficiently organize memories and actions by integrating individual sequences. It seems like the basal ganglia implement the “chunking.” The basal ganglia are known to include two major pathways, the direct and the indirect. Scientists found that these two pathways show similar activities during the initiation of movement, but show differential activations during the execution of behavioral sequences. Interestingly, basal ganglia circuits are implicated in Parkinson’s and Huntington’s disorders, in which learning of sequences are compromised. Further studies will reveal a more mechanistic understanding of sequence integration in the brain and potential interventions to enhance it in neurological disorders.

Single Gene Separates Queen from Workers

Ubx promotes corbicular development in Apis mellifera
Medved V. et al. Biology Letters, Jan 2014

In a hive of honey bees, the queen and worker bees have very different jobs. A new study shows that a single gene called Ultrbithrox (Ubx) separates a queen from worker bees. The Ubx gene was previously known to control leg and hindquarter development in bees. Interestingly, researchers now identified three functions for Ubx specific to worker bees. First, Ubx promotes the development of a smooth spot on the hind legs where the “pollen baskets” are located. Second, Ubx directs the formation of eleven perfectly spaced bristles on the section of the leg called the “pollen comb.” Third, Ubx mediates the formation of the “pollen press” which is a protrusion that helps pack and transport pollen back to the hive. Essentially, the Ubx gene promotes the development of three different physical structures on worker bees so that they can collect and transport pollen. Researchers confirmed these findings by silencing the Ubx gene genetically in worker bees and found that specialized leg features, including pollen combs and pollen presses, completely disappeared in the absence of the Ubx gene. Moreover, analyses of other bee species in the region revealed that the size and complexity of pollen baskets are directly correlated with the social behaviors of the particular bee species, suggesting that pollen baskets have yet-to-be-identified roles on the social behaviors of bees. Furthermore, the pollination of 35 percent of the world’s crops (with a $216 billion market value) depends on bees carrying pollen from one flower to another. This study might help us to develop new genetic approaches to make bees better, more efficient pollinators and to ultimately combat the worldwide pollination problem.

Molecular Switch in Aging Blood Cells Discovered

A canonical to non-canonical Wnt signaling switch in haematopoietic stem-cell ageing
Florian MC et al. Nature, October2013

Every single cell in our body ages over time. The aging of a cell is typically characterized by the progressive loss of physiological function and increased vulnerability to death. The aging of our cells/tissues/organs is the primary risk factor for any human diseases. One critical cell type that dramatically changes its properties during aging are blood stem cells, aka Hematopoietic Stem Cells (HSCs). Young HSCs have the capacity to differentiate into the diverse lineages of erythroid, lymphoid, and myeloid cells. Young HSCs are polarized (asymmetrical) cells, in which distinct cytoskeletal proteins (also called the “polarity complex”) are asymmetrically distributed within. However, the aged HSCs are mostly apolarized (symmetrical) cells and they differentiate only into lineages of myeloid cells (including, red blood cells, macrophages and monocytes) rather than lymphocytes (white blood cells in the immune system). The molecular changes in aging HSCs have largely been unknown. A recent study published in Nature shed some light onto the molecular identity of the ageing HSCs. Scientists showed that ageing HSCs have higher levels of a secreted protein called WNT5a, whereas the young HSCs have almost no WNT5a protein expressed in the cell. Moreover, the increased levels of WNT5a are found to attenuate the levels of the “polarity complex” proteins in HSCs and thus result in apolarized cells, which resemble the aging HSCs. Furthermore, transplantation studies revealed that increased WNT5a levels cause aging-related phenotypes and low Wnt5a levels promote a rejuvenation process in mice. These findings show that Wnt5a is the key molecule that controls the shift between young and old HSCs. Therapeutic approaches using antagonists of the Wnt5a molecule could potentially alleviate aging-related pathologies in the patients with a variety of blood diseases.

Hierarchy of hematopoietic stem cells

The blood system, also known as hematopoietic system, has enormous regenerative capacity to maintain functional mature blood cells that arise from highly proliferative but short-lived progenitor cells. Those progenitors in turn are generated from very rare blood stem cells called hematopoietic stem cells (HSCs). HSCs are one of the most studied stem cells in our body which has greatly shaped our thinking on the features of adult stem cells. These stem cells are kept at the bone marrow in close proximity to bone cells and other supporting cells forming the specialized home known as niche. In several aspects, a niche resembles a cellular stronghold that a queen lives in a safe and protected environment.

The interaction of stem cells with the niche is crucial as this prevents exhaustion of stem cells from uncontrolled cellular divisions and proliferation. While active progenitors account for the generation of mature blood cells, hematopoietic stem cells function as a reserved cell population. Interestingly, we observe the importance of the balance between those two cell populations in the aging process. Although the number of HSCs increases in aged animals, there is a decline in self-renewal of HSCs.

Other protective mechanisms include the low proliferation rates of HSCs in a relatively quiescent state, residing in a low oxygen environment [3], a relatively low degree of metabolism and preferential use of glycolysis as energy source, and additional protection mechanism against oxidative stress.

Low in oxygen but a good place to be!

Stem cells as the cell bank of the body are protected against internal and external insults by a number of mechanisms. Stem cell niche not only provides an environment that they can survive but also poses the lesser degree of internal and external insults. Those possible stresses on cells include, but not limited to, UV exposure, radiation, toxic chemicals, and free oxygen species that cause various damages in the cell including mutations in DNA (Fig. 3). Cells respond to those external and internal issues by various ways such as senescence (loss of stem cell activity), cell death or DNA repair. For example, blood stem cells mainly house in the bone marrow next to osteoblastic lining (blood-forming cells) and endothelial cells where they form the hypoxic (low oxygen tension) endosteal region. This hypoxic niche of HSCs provides lower levels of oxygen so that there are lower levels of free oxygen radicals that mainly arise from electrons leaking from mitochondria during oxidative phosphorylation. In addition, it has been shown that HSC express higher levels of hypoxia inducible factor-1α, a master regulator at low oxygen tension with hundreds of downstream targets regulating various aspects of metabolism including defense against oxidative stress and survival at low oxygen environment. It has also been shown that hypoxia increases self-renewal abilities of HSCs, thus keeps them healthy and functional for longer periods.

Protection from detrimental effects of reactive oxygen species (ROS)

Excess amounts of reactive oxygen species are detrimental to cells. ROS are found to cause hematopoietic stem cell defects as shown in mouse lacking FoxO and Atm genes. In those mutant mice, the hematopoietic defects could be rescued by the use of an antioxidant N-acetyl-cysteine. Anti-oxidants are one of the scavengers that diminish unwanted effects of reactive oxygen species. A number of fruits and vegetables such as beans, blueberry, strawberry, and apple are known with their high content of anti-oxidants. It is amazing to observe anti-oxidants being placed into our sustenance just as much as in some special genes (such as SOD2 and Hypoxia Inducible factor-2α) that provide additional protection for cells. Amazingly, stem cells show high levels of ROS scavenger genes.

Low metabolism provide protection for stem cells

Recent studies demonstrate that hematopoietic stem cells have lower rates metabolism as measured by lower oxygen consumption, lower ATP content and higher lactate production (an end product of cytoplasmic glycolysis) [4]. This means that stem cells produce and consume lesser energy (ATP) compared to more differentiated cells and the by-products of the energy production are kept lower. As higher energy demand brings higher rates of internal insults like production of ROS which is associated with aging and cellular damages, HSCs are granted with another protective mechanism by preferential use of glycolysis (anaerobic) instead of oxidative phosphorylation (aerobic).

Hematopoietic stem cells are quiescent

Another defense mechanism is the quiescence of stem cells which is associated with slow cell-cycle progression. Quiescence of stem cells means that they are kept at a resting, inactive state thus sustaining a self-renewing HSC compartment for life. Because when cell divides, they have to undergo thousands of chemical reactions including making a copy of the three billion letter long DNA, which puts cells at risk to get mutations. Thus, they don’t undergo division unless there is a stimulus. In addition, it has been found that HSCs divide only once every 145 days on average.

There are a number of studies indicating that there are signals in the niche that keeps HSCs in a quiescent state. Tie2/Ang-1 signaling, for instance, has been demonstrated to contribute to the maintenance of HSCs by inducing quiescence. While Ang-1 is expressed in the mesenchymal/stromal cells of niche, its receptor Tie2 is expressed at HSCs. In addition, it has been shown that Ang-1 can inhibit HSC division in culture and promote quiescence of HSCs in the bone marrow [5].

It is also reported that the cell adhesion molecules that allow physical interaction between stem cells and their niche components may participate in regulation of stem cell quiescence through a process called contact dependent inhibition of proliferation. For instance, it has been found that cell adhesion molecules such as N-cadherin, β1-integrin, and osteopontin might be involved in the regulation of cell cycle status of HSCs [6].

One advantage of quiescence of HSC comes from the lower susceptibility of slowly proliferating cells to radiation than other cells due to the expression of cell cycle inhibitors like p21 and anti-apoptotic (controlled cell death) machinery like ATM in HSCs. In addition, studies in p21 (a cell cycle inhibitor gene) knockout mice suggest that maintaining cell cycle quiescence is directly linked to self-renewal of HSCs [7].

Toxics are exported from hematopoietic stem cells

There are other issues concerning external insults against toxics and unwanted chemicals. An HSC population described as side population has been equipped with a number of transporters such as ATP Binding Cassette (ABC) transporters, P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) on their membrane providing high efflux ability [8]. They play an important role in the excretion of drugs and endogenous compounds. Those transporters work actively when there is an entrance or excess of such chemicals thus keeping damage minimal.

HSCs are placed in such an environment that even minimum damages by internal and external insults are prevented by different defense mechanisms including residing HSCs in the hypoxic niche, expression of ROS scavenger genes, preferential use of glycolytic metabolism, quiescence nature of HSCs, and removal of toxins by ABC transporters. It is very wise to home such an important cell in a place where it can prosper with a carefully balanced rate of cell division and metabolism. Hypoxic niche seems key to the protection of hematopoietic stem cells by supporting self-renewal and preservation of hematopoietic functions both at the same time. The presence of these protective systems that are graciously placed in our cells with perfect measurements provides an elusive mechanism to ensure healthy life-long reservoir of HSCs.

Ali Fethi Toprak is a PhD candidate at Southwestern Medical Center, Texas University.

Selected References

1. Kobayashi, C.I. and T. Suda, Regulation of reactive oxygen species in stem cells and cancer stem cells. J Cell Physiol, 2012. 227(2): p. 421-30.

2. Li, L. and H. Clevers, Coexistence of quiescent and active adult stem cells in mammals. Science, 2010. 327(5965): p. 542-5.

3. Eliasson, P. and J.I. Jonsson, The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol. 222(1): p. 17-22.

4. Simsek, T., et al., The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche. Cell Stem Cell, 2010. 7(3): p. 380-390.

5. Arai, F., et al., Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell, 2004. 118(2): p. 149-61.

6. Yamashita, Y.M., D.L. Jones, and M.T. Fuller, Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science, 2003. 301(5639): p. 1547-50.

7. Cheng, T., et al., Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science, 2000. 287(5459): p. 1804-8.

8. Huls, M., F.G. Russel, and R. Masereeuw, The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther, 2009. 328(1): p. 3-9.

9. Antioxidant Riches Found in Unexpected Foods. Retrieved from http://www.webmd.com/food-recipes/news/20040617/antioxidants-found-unexpected-foods, January 31, 2012.