Basics: Neurulation

When we had last seen our basic embryo, it had gone through gastrulation — a process in which cells of a two-layered sheet had moved inward, setting up the three germ layers (endoderm, mesoderm, and ectoderm) of the early embryo. In particular, cells at the organizer, a tissue that induces or organizes migrating cells, had rolled inwards to set up specific axial mesoderm structures: the prechordal plate, which will underlie cranial structures, and the notochord, which resides under the future hindbrain and spinal cord. At this point, the embryo has an outer layer of ectoderm, and lying under part of it, a band of prechordal mesoderm and notochord. In addition, the ectoderm is loaded with a molecule called BMP-4, a member of the TGF-β family of signaling molecules, and under its influence will go on to make skin, not nervous system. So what next?

In the absence of BMP-4, the ectoderm will instead become neuralized: it will make nervous system derivatives rather than skin. The organizer and that band of axial mesoderm are secreting molecules that inactivate BMP-4, called noggin, chordin, and follistatin (Wnt-3a and FGF are also important in more caudal regions of the nervous system). What we have is a system where all of the ectoderm is instructed to make skin, but one discrete stripe of mesoderm is emitting a signal to the ectoderm directly above it, overriding that instruction and encouraging the ectoderm to make a parallel stripe of neural tissue, instead.

The first overt response of the ectodermal tissue is for the cells to change shape. At this point, the ectoderm is a continuous sheet, where the cells are adherent to one another in a single layer; they are going to undergo coordinated shape changes to drive movement as a whole. All of the cells first become columnar, as you can see in the second diagram in this series, forming a neural plate:

Cells then change from a columnar shape to forming an apical constriction on the dorsal side—this shape change causes the sheet to buckle and bend inwards (there's also a pattern of cell migration by ectodermal cells towards the dorsal midline that also puts pressure on the neural plate to fold). The sheet of neural cells rolls up until its edges meet, making a neural tube. The fluid filled space in the middle will become the central canal of the spinal cord and the ventricles of the brain.

The diagram below illustrates that there are some subtle differences in different animals. Amphibians, reptiles, birds, and mammals all make a lovely and obvious tube when they fold up, but fish are a little less overt—their neural cells are tightly adherent and don't expose a space as they fold, although the cell movements are very similar. They secondarily cavitate to form the essential central canal. This diagram illustrates another critical phenomenon, though: what happens at the dorsal seam, where the edges of the folding tube meet?

At the edges of that dorsal midline, cells have to sort themselves out. Some will stick to the non-neural ectoderm and separate from the neural ectoderm, and form the epidermal epithelium. Others will stick with the neural ectoderm, and become part of the neural tube epithelium. Of unusual significance, though, are some in-between cells that are sort of 'left over' when the two epithelial sheets separate—they form a loose aggregate in the space between the skin and the neural tube, and have some unique properties. These are called neural crest cells, and at some time I'm going to have to write a Basics post just about them. They are a fascinating and important set of plastic cells that have great roles to play in both chordate development and evolution.

The closure of the neural tube is a critical point in development, and failures are depressingly common, occurring in about 1 in a thousand human births. Along the length of the mammalian nervous system, the tube typically closes up at a couple of points first, and then zippers itself up in between. If the edges fail to meet and fuse, the tube remains open to the external environment, which is most definitely not good. If the posterior end fails to close, the condition is called spina bifida. Spina bifida affects individuals to varying degrees depending on how much of the tube is left open; neural tube exposure is associated with nervous tissue damage in the affected area of the spinal cord, leading to anything from minor loss of sensation in the lower limbs to complete paralysis.

Failure of the anterior end of the neural tube is even more devastating. The fetal forebrain is exposed to the amniotic fluid, and fails to develop and degenerates, and the skull itself does not close over. This condition is called anencephaly, and it is lethal.

Assuming closure goes well, as it does most of the time, the end result is a hollow tube of neural epithelium suspended between an ectodermal epithelium dorsally and a notochord or prechordal plate ventrally. Signaling continues; remember that the epidermis is permeated with BMP4, and this BMP4 is going to induce a new signaling center in the neural tube, the roofplate, which is also going to secrete BMP4. Meanwhile, the notochord is also sending signals, and induces a floor plate in the ventral floor of the neural tube; the key molecule here is Sonic hedgehog, or Shh.

The double gradient — BMP4 spreading ventrally from the dorsal midline, Shh spreading dorsally from the ventral midline — sets up a pattern of regional specification, where the identity of neurons in the tube can be determined by just 'reading' the relative concentrations of the two factors. In addition, identity along the longitudinal axis is specified by the pattern of expression of the Hox genes. The process of neurulation sets aside a tube of tissue dedicated to forming the central nervous system, and establishes a dorsal-ventral and anterior-posterior coordinate system that allows cells to be parceled into unique fates.