The embryo is initially formed through fertilization, which occurs when a sperm cell and an egg cell unite into a single cell. This fertilized egg cell, or zygote, starts dividing through the process of mitosis to generate the cells that make up an entire organism. Sixteen days after fertilization, the developing embryo’s cells belong to one of three layers that form into the different tissues in the body (Betts et al., 2022). The endoderm, or inner tissue, is responsible for generating the lining tissues of various spaces within the body, such as the mucosae of the digestive and respiratory systems. The mesoderm, or middle tissue, gives rise to most of the muscle and connective tissues. Finally the ectoderm, or outer tissue, develops into the body’s outer layer of skin, hair, nails, as well as the nervous system. It is probably easy to see that the outer tissue of the embryo becomes the outer covering of the body, but how is it responsible for the nervous system?^[1]

Neural Tube

Two weeks into embryonic development, the human nervous system begins to form. As the embryo develops, a portion of the ectoderm differentiates into a specialized region of neuroectoderm, which is the precursor for the tissue of the nervous system (Betts et al., 2022). Cells in this region form a neural plate that begins to fold inward to form a neural groove that is lined on each side by a neural fold. These two neural folds eventually fuse together to form the neural tube (Figure 1) and set up the development of the brain and spinal cord. Cells from the neural folds then separate from the ectoderm to form a cluster of cells referred to as the neural crest, which runs lateral to the neural tube. These neural crest cells migrate away from the nascent central nervous system (CNS) that will form along the neural groove and develop into several parts of the peripheral nervous system (PNS) including the enteric nervous system that governs the function of the gastrointestinal tract.

During the third week of embryonic development, the anterior end of the neural tube begins developing into the brain, and the posterior portion begins developing into the spinal cord. This basic arrangement of tissue in the nervous system gives rise to more complex structures by the fourth week of development.^[2]

Primary Vesicles

As the anterior end of the neural tube starts to develop into the brain, it generates three primary vesicles: the forebrain (prosencephalon), the midbrain (mesencephalon), and the hindbrain (rhombencephalon) (Betts et al., 2022). The forebrain is the upper-most vesicle, the midbrain is the next vesicle, and the hindbrain is the lowest vesicle. One way of thinking about how the brain is arranged is to use these three regions—forebrain, midbrain, and hindbrain (Figure 2).^[3]

Secondary Vesicles

By week 5, the three primary vesicles differentiate further into five secondary vesicles (Betts et al., 2022) (Figure 2). The forebrain enlarges into two new vesicles called the telencephalon and the diencephalon. The telencephalon will become the cerebrum—the largest part of the adult brain which contains the lobes of the cerebral cortex, hippocampus, and basal ganglia. The diencephalon will give rise to several structures including the thalamus (the central relay hub for sensory signals) and hypothalamus (involved in homeostasis and regulating functions including hunger, sleep, and mood).

A third secondary vesicle, the mesencephalon or midbrain, is composed of the tectum, the cerebral aqueduct, the tegmentum, and the cerebral peduncles. The midbrain is an established region of the brain at the primary vesicle stage and does not further differentiate into finer divisions. The rest of the brain develops around the midbrain, which is involved in many functions including head and eye movements, motivation, and reward.

The hindbrain develops into the final secondary vesicles, the metencephalon and myelencephalon. The metencephalon gives rise to the pons and cerebellum. The cerebellum accounts for about 10 percent of the mass of the brain and is an important structure for coordinated movement, posture, as well as cognition. The cerebellum connects to the rest of the brain via the pons, because the pons and cerebellum develop out of the same vesicle. Finally, the myelencephalon gives rise to the adult structure known as the medulla oblongata (involved in breathing, digestion, heart rate, blood pressure, etc.). The structures that arise from the midbrain and hindbrain, except for the cerebellum, are collectively considered the brain stem, which specifically includes the midbrain, pons, and medulla.

We first learned about the above structures in Chapter 2: The Brain and Nervous System. In order to understand the outcome of fetal brain development, it may be helpful to return to Chapter 2 to review details of these structures in the adult brain.^[4]