Human embryogenesis

Embryogenesis, the first eight weeks of development after fertilization, is an incredibly complicated process. It’s amazing that in eight weeks we’re transforming from a single cell to an organism with a multi-level body plan. The circulatory, excretory, and neurologic systems all begin to develop during this stage. Luckily, like with many complex biological concepts, fertilization can be broken down into smaller, simpler ideas. The big idea of embryogenesis is going from a single cell to a ball of cells to a set of tubes.

The zygote’s first priority is dividing to make lots of new cells, so it’s first few days are spent in rapid mitotic division. With each round of division, it doubles in cell number, so the cell number is increasing at an exponential rate! This division is taking place so quickly that the cells don’t have time to grow, so the 32 cell stage known as the morula is the same size as the zygote. At this point, the zona pellucida (a protective membrane of glycoproteins that had surrounded the egg cell) is still intact, which also limits how big it can grow.

Around day 4, cells continue to divide, but they also begin to differentiate and develop more specific forms and functions. When a cell differentiates, it moves down a certain path toward being a specific type of cell (e.g. an ear cell or a kidney cell), and this process (99% of the time) only goes in one direction. Two layers develop: an outer shell layer known as the trophoblast, and an inner collection of cells called the inner cell mass. Rather than being arranged in a solid sphere of cells, the inner cell mass is pushed off to one side of the sphere formed by the trophoblast. The rest of the fluid-filled cavity is called the blastocoel, and the whole setup resembles a snow globe. The outer trophoblast will develop into structures that help the growing embryo implant in the mother’s uterus. The inner cell mass will continue to differentiate and parts of it will eventually become the embryo, so it is sometimes called the embryoblast (the suffix “blast” means “to make”). This is also the time when the zona pellucida begins to disappear, allowing the ball of cells, now called a blastocyst, to grow and change shape. In non-mammal animals, the term for this stage is “blastula”, but we will stick with terms that apply to human development for the purposes of this discussion.

At this point, cells in the inner cell mass are pluripotent, meaning they can eventually turn into the cells of any body tissue (muscle, brain, bone, etc). During the second week, these cells differentiate further into the epiblast and the hypoblast, which are the two layers of the bilaminar disc. This disc is a flat slice across the developing sphere, and splits the environment into two cavities. The hypoblast is the layer facing the blastocoel, while the epiblast is on the other side. Let’s imagine each of these layers as a flat balloon. The balloons expand to fill the space, and become the two new cavities: the primitive yolk sac on the side of the hypoblast and the amniotic cavity on the side of epiblast. The amniotic cavity will eventually surround the fetus.

Quick recap: the outermost layer of the sphere is the trophoblast. Inside the sphere are two spaces that are each lined by either the hypoblast or the epiblast. The point where the epiblast and hypoblast press up against each other is known as the bilaminar disc, and this disk is what splits the sphere to make the two cavities.

The hypoblast does not contribute to the embryo, so we will now turn our focus solely on the epiblast.

Week 3 of development is the week of gastrulation. A germ layer is a layer of cells that will go on to form one of our organizational tubes. Our anatomy can really be boiled down to an inner tube (our digestive tract), and a series of tubes that wrap around it. The three germ layers that will translate into these tubes are the ectoderm, the mesoderm, and the endoderm.

The first step of gastrulation is the formation of the primitive streak (~ day 16). Let’s imagine the bilaminar disc as two tier cake. Imagine taking a knife and cutting into just the top layer (the epiblast) like you’re going to cut a slice.

This cut is the primitive streak, and it cuts from the caudal (anus) end in toward the end that will eventually become the head (the rostral end). This streak determines the midline of the body, and separates the left and right sides. Like all deuterostomes, humans have bilateral symmetry, which means that there is a single across which we can split ourselves to make mirror images. What we are actually seeing when we look at a primitive streak are moving cells. They are going from the epiblast and moving down so they end up between the original epiblast layer and the hypoblast. I’ve always imagined the motion like water falling down a waterfall. The first layer to invaginate dives the deepest and ends up closest to the hypoblast – this is the endoderm. The next layers will become the mesoderm, and the cells of the epiblast that continue to border the amniotic cavity are the ectoderm. We now have three germ layers, all of which will contribute to the developing embryo. In the picture below, the anus end is facing us.

Directly beneath the primitive streak the mesoderm (the middle germ layer) forms a thin rod of cells known as the notochord. The notochord helps define the major axis of our bodies, and is important in inducing the next step of embryogenesis, when we finally start to make our tubes! The notochord is a defining feature of the Chordate phylum, and will eventually become our intervertebral discs.

All this and we still haven’t made tubes! Now that we have successfully made the cell layers, we have to create the final 3D product. The first step in this rolling is the creation of the notochord. The notochord causes the ectoderm above it to form a thick flat plate of cells called the neural plate. The neural plate extends the length of the rostral-caudal axis. The neural plate then bends back on itself and seals itself into a tube known as the neural tube that fits underneath the ectoderm. The borders of where the neural plate had been get pulled under with it, and become the neural crest. The neural tube will become the brain and spinal cord.

The neural crest is sometimes called the fourth germ layer, because the cells that become the sympathetic and parasympathetic nervous systems, melanocytes, Schwann cells, even some of the bones and connective tissue of the face.

Meanwhile, the mesoderm can be subdivided into the axial, paraxial, intermediate, and lateral plate mesoderms. The notochord came from the axial mesoderm. The paraxial mesoderm will give rise to somites, which will differentiate into muscle, cartilage, bone, and dermis. Somite derivatives create a segmented body plan (see right). The intermediate mesoderm is the origin of our urogenital system – our kidneys, gonads, adrenal glands, and the ducts that connect them. The lateral plate mesoderm will give rise to the heart (the first organ to develop!), blood vessels, the body wall, and the muscle in our organs.

Also at the same time, the endoderm is rolling into a tube as well – the digestive tract. The digestive tract is subdivided into the foregut, midgut, and hindgut. Each subdivision has its own nerve and blood supply. Organs related to the GI tract actually start off as outpouchings of this tube. The foregut gives rise to the esophagus, stomach, part of the duodenum, and the respiratory bud, which will eventually develop into the lungs. The second half of the duodenum through to the transverse colon arise from the midgut. The remainder of the GI tract, including the rest of the transverse colon, the descending colon, the sigmoid colon, and the rectum are formed from the hindgut.

That’s what is going in with each of the three layers. While this is happening, the mesodermal layers are circling around the endoderm, and the part of the ectoderm that will become the skin is circling around both of the other layers. Some tubes, likes the neural tube, are closing, while the gut tube is connecting to the ectoderm to form the mouth and the anus. By the time eight weeks have passed, all of our tubes are in order, the primitive heart has been beating for almost five weeks, and development is well on its way!

The gut tube is the only developmental tube that is supposed to remain an open cylinder. If the neural tube does not close, it creates a life-threatening condition known as spina bifida. Spina bifida can occur due to genetic factors, but may also be caused by a lack of folic acid during pregnancy or if the mother has uncontrolled diabetes. Spina bifida can lead to weakness and paralysis of the legs, bladder and bowel control issues, and other physical problems. Children with spina bifida often struggle academically, potentially due to problems in the development of the central nervous system. While there is no known cure for spina bifida, the introduction of folic acid into everyday foods like cereal and bread has drastically reduced the incidence of neural tube defects in newborns.