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I came across this post on The Node with some fantastic imaging from Zelzer and colleagues at the Weizmann of the cells that connect tendon to bone.  The paper sheds light on the developmental origins of the cells that form the eminences; the units that connect tendon to bone. As it turns out, these do not originate from cartilage (chondrocytes), as previously thought, but instead from a separate lineage specified slightly later in development.  These progenitor cells can be identified by the genes they express.  In the image below, the arrows point to these cells, represented in green [Sox9-positive (green), Col2a1-negative (red)].

Blitz et al. 2013 Development 10.1242/dev.093906

Brains are made up of many different types of cells that come about through common stem cells called neuroblast progenitors. These progenitors can produce the number and diversity of cell types necessary to form a central nervous system. As neuroblasts divide to make more cells, they can potentially specify different types of cells with each round of division, and depending upon the stage of development. 

Lineage development from larva to adult. Cartoon diagram highlighting a single neural lineage in the larval brain (left) and in the adult brain (right). Note the decreased contribution of primary neurons in the adult brain compared to the larval brain. GMC ganglion mother cell. Spindler and Hartenstein, Dev Genes Evol. 2010 220: 1–10. doi: 10.1007/s00427-010-0323-7

In the fruit fly, most of the cells in the adult central nervous system have been mapped back to their embyonic neuroblast progenitor, of which there are about 100 or so. As such, the fruit fly brain is a popular model for understanding neural circuitry and development. One of the better-studied neuroblast lineages, referred to as NB7-1, gives rise to seven progenitor cells, the first five of which give rise to lineages of motorneurons that will wire the nervous system to the muscles. The remaining two neuroblasts give rise to interneurons; the cells that connect neurons within the nervous system.

Though not innervated by NB7-1 motorneurons, these are  developing flight muscles of the fruit fly (visualised in GREEN), which are remodeled from larval muscle templates by the fusion of adult muscle precursors (visualised in BLUE). The motor neurons (visualised in RED) of the larval muscles are re-specified to innervate the flight muscles. These muscles and motor neurons are a unique example of how adult structures are refashioned from embryonic counterparts during metamorphosis in animals. Imaged by: S. Roy (Institute of Molecular and Cell Biology, Singapore; Cover image, EMBO J, 08.08.2007)

Each of the five motorneuron-specifying neuroblasts gives rise to a different lineage of cells. The lineages specified in the first two neuroblasts, called U1 and U2, are governed by a gene called hunchback (hb), which is normally only active in the first two progenitors. The hb gene codes for a protein that regulates the activity of other genes called a transcription factorTranscription factors work by recognising DNA sequences in a gene’s promoter; the bit immediately preceding the coding sequence to a gene. Once bound to the promoter, they summon the molecular machinery (or are sometimes already pre-assembled to it) necessary to decode that gene into a template to make a protein. In some cases, like with hb, transcription factors (the proteins) bind to their own gene promoters. This is usually done to ensure that a lot of that particular transcription factor is produced, as it may be necessary to activate a great number of downstream genes. In fact, some transcription factors are responsible for turning on a whole cascades of gene activity; in some cases altering the identity of a lineage of cells.

In fact, if hb is experimentally turned on in any of the first five progenitors, it will turn on the same U1/U2 motorneuron identity in these cells. Curiously though, hb’s affect is limited to those cells as the remaining two (interneuron-specifying) progenitors and their resulting neurons do not respond to the hb signal. When a sub-group of cells is capable of responding to an inductive signal like this, it is said to be competent.

Chris Doe’s group at the Howard Hughes Medical Institute utilises this predictable progression of neuronal specification to understand how competence is regulated in cells. As the identity of each cell has been mapped from the embryo through larval stages and on to the adult, NB7-1 gives us a system to understand how cellular identity is fundamentally achieved at the genetic level. So the next time someone flips off fly research within earshot, enlighten them.

So if hb‘s job is to turn on the genes involved in the U1/U2 motorneuron program, why can the first five cells respond, but not the other two? Remember that the DNA is very highly packaged and organised within the cell. There are a number of ways that the cell can organise a specific region of DNA on a chromosome in order to ensure it is ready for activity when necessary. One of the mechanisms involves specifically positioning different regions of chromosomes in different parts of the nucleus. This filing system is not entirely different than that used by most first year university students in determining if clothes are still wearable (I’ll speak for the men here):  the pile of clothes on the floor in the middle of the room (though subject to a smell-test) are fair game. The clothes on the edges of the room; still on their shelves and hung up in the closet, like that sweater your lovely Aunt [so-and-so] knitted you for Christmas last year, are out of the way and generally not (read: never, in the case of the sweater) used. In a similar way, by tethering regions of a chromosome to the edge of the nucleus, to a structure called the nuclear lamina, they’re effectively inaccessible, no matter what transcription factor proteins are available to decode those regions.

Chris Doe’s group recently published findings that show that in the first two progenitors, the hb gene is physically positioned in the interior of the nucleus, a region that promotes its activity. In the 3rd, 4th and 5th progenitors, the gene is silent but remains poised in the interior (ie. it failed the smell-test; it remains on the dorm floor) and responsive to hb-induction. After the 5th division, hb gets repositioned to the edge of the nucleus (right next to the sweater) where it is silenced. This positioning is inherited by any of the future cells in that neuroblast’s lineage, ensuring that they hb protein is no longer produced in these cells. Experimentally interfering with this repositioning enables more cells to respond to the hb signal, resulting in the production in a greater number of U1/U2 motorneurons. This adds to the growing body of examples of genes that are regulated in a developmentally-relevant and heritable manner by tethering to the nuclear lamina. This also provides a mechanistic frame work to understand developmental competence at the molecular level in cells. 

June 2017
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