In the Beginning
All human beings begin life as a fertilized egg, called a zygote, which is a single cell about one-fifth the size of the period at the end of this sentence. By adulthood, the human body has grown to more than a hundred trillion cells, most of which are highly specialized for particular tasks. Embyrological development is delicate but finely honed process, with elegant choreography that produces amazingly few mistakes. Massive proliferation allows for rapid growth throughout embryological development, and the newborn cells integrate chemical and genetic signals to determine their specialization. In general, the more complex an organism is, the longer it develops in utero. The newborn animal arrives with only some fine-tuning left to do, like building up its immune system and refining its neural circuitry. Research over the past seventy years has offered much insight into both the general principles and the species-specific rules of development, starting with the very first step to becoming multicellular.

gastrulationOne part of development that is common to all multicellular organisms is mitosis, which is the process of cell division. Cells reproduce themselves exactly, and the result is exponential growth. The zygote divides into two cells, then two become four, four become eight, and eight become sixteen, and so forth. In many species, the embryo forms a hollow structure called the blastula during the earliest stages of development. Cells from the surface of the blastula move to the interior to form layers. The layers redistribute themselves as the blastula invaginates during gastrulation, when a portion of the surface cells turn inward and the three germ layers that form all adult tissues are established. The endoderm is the innermost layer, which gives rise to the gut, lungs and liver. The mesoderm is the middle layer, which gives rise to skeletal system, and muscle and vascular regions. The ectoderm is the outermost layer, which gives rise to both the central and peripheral nervous systems as well as the epidermis. Following gastrulation is neurulation, the process that initiates the formation of the nervous system.

Forming the Nervous System
The neurons and glial cells that make up the central nervous system (CNS) originate from a specialized region of the ectoderm, called the neural plate, which is located along the dorsal midline of the embryo. Around the third week of embryonic development, the mesoderm gives a molecular signal to begin neurulation. Soon after neural induction, the neural plate begins to fold inward from the side to from the neural groove, which fuses at the top of the embryo to form a hollow arrangement of cells called the neural tube. Failure to close the back end of the neural tube causes the condition known as spina bifida. If the neural tube does not close at its front end, the result is anencephaly, a condition in which the gross brain structure is greatly disturbed.

neurolationThe cells that line the inside of the neural tube are called neuroepithelium, and they will eventually form the neurons in the brain and spinal cord. In addition, cells within the neuroepithelium also give rise to a specialized group of migratory cells, called the neural crest. Neural crest cells leave the neural tube soon after it has closed and migrate away to form a wide variety of peripheral tissues, such as the sympathetic and parasympathetic ganglia. Inside the tube, the cells continue to proliferate rapidly, though the rate varies along the tube depending on which CNS structures are being formed. The cortex, which is the part of the brain that mediates higher functions like attention and voluntary movement, develops last.

Development of the Brain
The cortex is comprised of six layers of cells that form inside out from the deepest layer to the most superficial. The progenitor cells undergo mitosis at the luminal surface, dividing beneath the forming cortex. Once leaving the luminal surface, the neurons stop dividing and travel to their home in one of the six layers of cortex. Neurons that are born later in development must get past the deepest layers to reach the top, i.e., neurons destined for layer I of cortex must travel through the five previous layers to get to their final location. These migrating cortical neurons travel along radial glial cells, which stretch from the luminal surface to the uppermost pial surface. Once the cell bodies are in place, the neurons send out axons to make connections with other cells. At the tip of the sprouting axon is usually a growth cone. The growth cone acts as a kind of scout for the neuron, reading chemical messages from the surface beneath it and the signals from neighboring cells to determine where the axon is supposed to terminate. Thus, the complex circuitry of the brain gets wired efficiently and correctly.

Researchers have been especially interested in studying cortical development because the mechanisms involved are likely similar to those used for learning and memory. Also, neurons do not usually renew themselves the way somatic cells do. They undergo mitosis for the final time during embryological development and do not normally divide again. As my grade school teacher put it, “You are born with all the neurons you are going to get — use them wisely.” Recent research by Elizabeth Gould and colleagues suggests that it may be possible to form new neurons in adult primate brains, which would mean exciting news for people interested in treating human brain disorders that result from degeneration of neurons, such as Parkinson’s and Alzheimer’s Disease.

How Does A Cell Know What It Is Supposed To Be?
The human body is made up of trillions of cells that originate from the same single zygote, yet nearly all cells become specialized to carry out specific tasks. Given that each cell (with the exception of the lymphocytes) contains the same set of genes, how does one cell become a liver cell and another cell turn into a brain cell? The primary answer is that not all genes are activated in each cell. Nuclear proteins control the differential activation of specific genes within individual by binding to DNA sequences, thereby allowing particular sections of the gene to be transcribed. Sometimes nature takes an elegant short cut in gene regulation by putting one gene “in charge” of many other genes. These regulatory sequences, called homeobox genes, are like the first domino in a long line — once activated, they turn on a cascade of other genes. Research on Drosophila has proved especially fruitful for understanding the mechanisms of homeobox genes. It only takes a few genes to control the gross body plan of the fly.

Cell lineage is another important factor in differentiation. Rather than force each cell to go through the process of determining which genes to activate, nature makes some of the decisions early in development so that cells are already partially differentiated as they are still proliferating. Cells marked as internal organ tissue divide to produce more cells marked as internal organ tissue. Since there is no going backward in differentiation, this has the advantage of increasing the number of general kinds of cells while saving much of the fine-tuning for later in development. As noted above, neural tissues are quickly differentiated from other cell lines even before the individual cells are targeted to specific brain regions.

A third crucial factor in determining cell identity is cell-cell interactions. Cells can communicate with one another via molecular signals and alter their gene transcription on the basis of this communication. We have already seen an example of cell-cell interactions with the induction of neuralation in the ectoderm from signals in the mesoderm. Evidence also suggests that local cell interactions govern the differentiation of glial cells into Type 1 astrocytes, Type 2 astrocytes, or oligodendrocytes. If left alone in a culture dish, progenitors of the oligodendrocytes will develop only into oligodendrocytes. However, adding optic nerve extracts or proteins released by Type 1 astrocytes induces the formation of Type 2 astrocytes from the oligodendrocytes precursors. These and similar studies suggest that local cell interactions govern the later periods of cell differentiation.

This piece has focused on the remarkable and elegant manner in which complex organisms develop from just a single cell, but it is important to remember that development does not stop after birth. Even adults are still developing, as their bodies adjust to meet each new life stage. Though we will never recapture the kind of plasticity seen during embryological development, the human body has an amazing capacity to grow and change that remains present throughout the life span. Researchers seek to make connections between the processes used in embryological development and the mechanisms we use to adapt to our changing environment. The brain, for example, is constantly refining its connections to accommodate the learning we do every day. By identifying such parallels, the study of development informs us about the mechanisms of both rapid, individual changes and the slow process of evolution, thus giving us tremendous insight into who we are, where we have been and where we might be headed tomorrow.

Joanna Schaffhausen earned a B.S. in psychology from Tufts University in 1996. She is currently a graduate student at Yale University, interested in the cellular mechanisms of learning and memory.

References:
Gilbert, S.F. 1994, “Developmental Biology,” 4th ed. Sinauer Associates, Sunderland, MA.

Kandel, E. R., Schwartz, J. H, and Jessel, T. M. Principles of Neuroscience, Third Ed., Appleton & Lange, 1991.

Gould, E., Reeves, AJ, Fallah, M., Tanapat, P., Gross, CG, and Fuchs, E.(1999) “Hippcampal neurogenesis in adult Old World primates.” Proceedings of the National Academy of Sciences, USA 96(9): 5263-7.

Gould, E., Beylin, A., Tanapat, P., Reeves, A., and Shors, TJ. (1999) “Learning enhances adult neurogensis in hippocampal formation.” Nature Neuroscience, 2(3): 2605-9.