March 23, 2005. Biology 104. Albert Harris   Development of the central nervous system Some review of the concept of embryonic induction: Only certain cells are susceptible to being induced to differentiate into nerve cells: the technical name for this sensitivity is "competence"     This usage invented by C H Waddington "determination" means the degree of irreversibility of a given cell to differentiate into a certain cell type. It is an important fact that embryonic cells (and some adult "stem cells") always (always? I think so!) become determined before they actually differentiate. That means they haven't yet started making the special proteins, but they have somehow been "locked in" so that the only cell type they can form is decided. Some undifferentiated stem cells (especially in the bone marrow) have become determined to become one or other of the different kinds of blood cells, but potentially can become any of several. The term "stem cell" used to refer specifically to dividing populations of cells that had become "determined" (= irreversibly committed) to differentiate into 1 or a few differentiated cell types. This term stem cell has now been hijacked by the big debate about culturing undifferentiated cells from human embryos, and THOSE stem cells supposedly & ideally are not determined In my opinion, political grandstanding on both sides of this issue has caused scientists to exaggerate the potential of the method. They don't even ask how the differentiating cells would get geometrically arranged into the correct anatomical patterns. (Probably they would "sort out"!?) Nerve cells NEVER divide or even copy their DNA after forming axons and dendrites. So the development of the nervous system is mostly by cells that are determined but not differentiated. Notice also that if you invented methods for making nerves or other cells "DE-differentiate" (revert to pre-determination state) then that would be as good or better than embryonic stem cells. In bird embryos, all of development, including the folding of the neural tube occurs much earlier at the front end of the embryo, and then as a sort of time gradient, progressively posterior. Therefore, if you look at serial sections of a chick embryo at around 40 hours of development, & look at the rear sections first the result is as if you were seeing progressive development. The VADE MECUM CD disk that comes with the textbook contains a series of photos of serial sections of a 33 hour chick. Sometimes the neural folds don't adhere and fuse normally. This results in the (serious!) birth defect "spina bifida". (one baby in 500 suffers from this in the US; if the mother took enough folic acid (vitamin B12) the frequency of this birth defect is decreased by at least one half.) In the extreme cases, almost no brain develops ("anencephaly") Normal enlargement of the brain (and the eyeballs) depends on internal fluid pressure. (sort of like a balloon; where tensile stress is least, the brain bulges out more) Nerve cells = "neurons" cytoplasmic extensions crawl outward = "axons" and also "dendrites" Axons & dendrites = the equivalent of "wires" of the nervous system Their paths result from active locomotion of amoeboid tips called "growth cones" This concept was invented by the Spanish histologist, Santiago Ramon y Cajal. It was proven true by the American embryologist Ross Harrison, who invented tissue culture to do the key experiment (explanting pieces of frog nervous system into clotted lymph) The alternative hypotheses for how nerve fibers are formed were a) That they were secreted by surrounding cells (the supporting evidence probably was a misinterpretation of myelin formation) b) That axons were assembled out of pre-formed rods, of some kind. Ross Harrison's first experimental test was to inject masses of clotted lymph into developing embryos, and show that nerves still developed penetrating right through the (non-living, non-cellular) mass of clot protein. This should have convinced people, but it didn't convince them!. But that experiment gave Harrison the idea (and the courage) to do what amounts to the reverse experiment, to put nerves into clot outside the body. [& knowing about this earlier experiment gave me the idea, back in the 1980s, to inject masses of collagen into developing embryos, to test a theory that we will get to later in the course] In general, you can learn a lot from going back and reading the original research papers, even 100-years old in other languages . Because axons paths are created by active locomotion of amoeboid "nerve growth cones", therefore the 'wiring pattern' of the nervous system is created by whatever mechanisms steer this locomotion. When the nerve growth cone reaches its proper connection, it differentiates to form a synapse there. Motor nerves are in your spinal cord; & their growth cones "grow" (really, they crawl, of course) from there to your various muscle cells. Sensory nerves differentiate from neural crest cells, and send axons out to the surface of your skin, etc. Their cell bodies form ganglia next to the spinal cord, and other growth cones also grow back into the spinal cord to make synapses there. Notice that human axons can be 2 or 3 feet long; Depending how long your arms and legs are! If nerve fibers get cut (in an accident, or surgery!) then the part of each axon beyond the cut location always dies. They can't reconnect, but a new growth cone will usually develop at the cut end of the nerve, and this will crawl through your finger or leg etc. and "try" to find its way to the correct location where it should form a new synapse. Muscle cells will die if not reconnected to some motor nerve. In tissue culture cells, the following categories of guidance mechanisms have been found to occur: 1) Chemotaxis    guidance by gradients of chemical concentration 2) Haptotaxis    guidance by difference in adhesiveness 3) Contact guidance    guidance by fibers, ridges or grooves 4) Contact inhibition     inhibition of locomotion at cell-cell adhesions 5) Galvanotaxis    guidance or reorientation in response to voltages 6) "rugophobia" and "rugophilia"     (which hardly anybody cares about) 7) There are probably other mechanisms: you could discover! 8) 9) 10) In the late 1990s, I got a free trip to England (Canterbury) paid by a pharmaceutical company ("Ethicon") that makes special bandages and other materials intended to stimulate and steer cell locomotion and nerve fiber re-growth. They had been using some of the methods I developed long ago, that you saw in the video, and I was the "guest of honor" for a series of talks. That was what I did spring vacation that year! Ethicon calls its products "Intelligent Bandages" The important concept of "neural projections" a J b I c H d G e F f E g D h C i B j A Hundreds of examples exist in the nervous system in which nerves connect one area of the brain to another area, with the endings of the nerves connecting in a map-like pattern. The retina of the eye forms a neural projection to the roof of the midbrain of birds, amphibians and fish. That is called the "retino-tectal" projection. (and more research has been done on it than any other projection) Sensory nerves "project" from the skin to a certain area in the brain. Motor nerves project from an adjacent area to body muscles! The expansion of the brain (and also the eyeballs) is by internal fluid pressure, and adjustment of tension resistance.

 

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