CNS Development Case File

CNS Development Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 11

A 23-year-old graduate student brings her 20-month-old baby boy to the student health clinic. She is concerned that he doesn’t talk yet and still looks “small” for his age with a head that looks “tiny.” She noticed that he was a lot smaller than his peers in day care and has always been small since birth. Despite his size, he has gotten into trouble for his hyperactive behavior. On examination, the boy’s head measures 46 cm (5th percentile for age). Though both she and her boyfriend are more than 6 ft tall, their son is less than the 10th percentile in both height and weight. Examination of his face revealed small eyes and thin, smooth lips. The results of her prenatal tests from her college health clinic were normal. She notes that the pregnancy was unplanned and occurred during her senior year of college. The patient’s constellation of symptoms points to an early developmental insult, either from a genetic or congenital factor. The physician elicits a maternal history of alcohol consumption during the pregnancy.

• What is the most likely cause of the baby’s symptoms?
• What is the underlying mechanism of this disorder?
• Are there any preventative measures available?

ANSWERS TO CASE 11: CNS DEVELOPMENT

Summary: This young mother gave birth to a baby boy who has many developmental issues that affect his appearance (morphology), size (growth), and behavior (neurological development). She admitted to having “partied” too much and binge drinking during her senior year, even resulting in a conviction for intoxicated driving, but has since sought help and is now sober. Examination of the toddler revealed poor motor dexterity and coordination for his age as well as speech delay.

• Cause of the patient’s symptoms: Fetal alcohol syndrome (FAS) is a likely diagnosis. CNS manifestations of alcohol exposure result in structural deficits like small head circumference and facial abnormalities. The neurological sequelae can cause difficulty with motor and coordination tasks. The functional deficits can be the most detrimental: developmental delay, mental retardation, hyperactive behavior, problems with daily living, and poor reasoning and judgment.
• Underlying mechanism: Dysmorphia occurs when normal development of the organism is altered, resulting in features that are altered in shape, size, or positioning. Alcohol is a known teratogen that affects the development of the CNS, through the disruption of biochemical signals, altered gene expression, and changes in cell growth and survival. Despite the early developmental nature of the insult, the CNS deficits generally persist throughout the lifespan.
• Preventive measures: FAS is completely preventable—if a woman abstains from drinking alcohol while pregnant or when she could become pregnant. There is no level of alcohol that has been determined to be safe.
  

CLINICAL CORRELATIONS

FAS is one of the most common causes of mental retardation in the United States and is the most severe form of fetal alcohol spectrum disorders (FASDs). Data from the U.S. Centers of Disease Control and Prevention show FAS to have an incidence of 0.2–1.5 cases per 1000 live births. The scope of alcohol usage is widespread: more than half of women of childbearing age reported alcohol consumption in the past month. Most drank only occasionally, but 15% could be classified as moderate or heavy drinkers. Some 13% of woman had consumed five or more drinks on one occasion (binge drinking) in the last month. As nearly half of all US pregnancies are unintended, and millions of fertile women are sexually active without using adequate contraception, the risk for an alcohol-exposed pregnancy is significant, up to an estimated 2% of women annually. Diagnosis of FAS requires the presence of three hallmark characteristics: facial abnormalities, growth deficits, and CNS abnormalities. The CNS abnormalities can be subdivided into structural, neurological, and functional domains. FASDs represent a continuum of symptoms that range from the mildest functional perturbations to full-blown FAS, with all of them linked by early maternal alcohol consumption.

APPROACH TO CNS DEVELOPMENT

Objectives

1. Relate the various CNS developmental structures.
2. Know the sequence of events and temporal program.
3. Understand the tissue-specific signals involved.

Definitions

Ectoderm: The outermost of the three main embryonic germ cell layers which gives rise to the tissues of the central and peripheral nervous system as well as skin. The endoderm, or innermost layer, generates the gut, lungs, and liver. The mesoderm, or middle layer, develops into muscle, the vascular system, and connective tissue.

Neural plate: The earliest structure formed in the CNS, which appears as a shoe-shaped thickening of the ectoderm beginning around the third week of development.

Neural groove: A length-wise invagination of the neural plate that occurs soon after the plate is formed.

Neural tube: The lateral edges of the groove form the neural folds which become elevated, approach the midline, and fuse together to form a tubelike structure. This fusion first occurs in the cervical region and proceeds in both cranial and caudal directions, finishing around the 27th day of gestation.

Forebrain (prosencephalon): The cranial end of the neural tube forms three distinct dilations, with the forebrain being the most cranial. It later forms the telencephalon which later develops into the cerebral hemispheres (most rostral) and the diencephalon, which includes the thalamus, hypothalamus, epithalamus, and posterior pituitary.

Midbrain (mesencephalon): This is the second dilation of the neural tube.

Hindbrain (rhombencephalon): The third and most caudal of the initial dilations and consists of two parts, the metencephalon which later forms the pons and cerebellum, and the more caudal myelencephalon, which becomes the medulla. The spinal cord develops later from the most caudal portion of the neural tube.

Notochord: A mesodermal structure that lies ventral to the neural tube and induces the formation of ventral neural structures.

Differentiation: The process of progressive changes that a cell undergoes to mature from a cell that has the ability to become multiple cell types into a cell with a more restricted fate.

Inducing factors: Inducing factors are signaling molecules that are provided by other cells that can influence the differentiation of a particular cell.

Competence: The ability of a cell to respond to developmental signals like inducing factors.

DISCUSSION

The central nervous system (CNS) forms through progressive rounds of differentiation which are orchestrated by a series of exposures to signals mediated by inducing factors. One of the earliest stages is the segregation of a population of ectodermal cells which will become neural tissue from others that will become epidermis. This differentiation of ectoderm is mediated by exposure to inductive signals from underlying mesoderm that block the activity of a family of growth factors called bone morphogenetic proteins (BMPs), causing the ectoderm to form neural tissue. Examples of these protein signals include: chordin, noggin, and follistatin. Cells that do not receive these signals develop into epidermis, and can no longer form neural structures.

Once these cells become committed to become neural tissue, they coalesce to form the neural plate (see Figure 11-1). Within the neural plate, further signaling occurs that organizes the cell fates of these neural cells based upon their location within the plate. Through the process of neurulation, the neural plate invaginates to form the neural groove, which subsequently fuses into a complete neural tube. The elevation of the lateral edges of the groove is the first sign of brain development. Two major axes become important for the specification of neural identity. The medial-lateral axis in the flat neural plate develops into the dorsoventral axis in the closed neural tube. The rostrocaudal axis running the length of the organism determines the four major subdivisions within the CNS (from rostral to caudal): forebrain, midbrain, hindbrain, and spinal cord. The rostral two-thirds of the neural tube develop into the brain, while the caudal one-third develops into the spinal cord. Failure of the cranial closure results in a condition called anencephaly.

The dorsoventral axis in the developing CNS relies upon further inductive factors produced by nonneural mesodermal cells. The notochord, a ventral midline structure composed of mesoderm produces the inducing factor, sonic hedgehog, which then signals the neurons in the ventral neural tube to form motor neurons and ventral interneurons. In a complementary fashion, cells in the dorsal epidermal ectoderm produce several BMPs that pattern the dorsal neural tube to form dorsal sensory interneurons. In a piece of developmental alchemy, the amount or concentration of these inducing signals sets up gradients along the dorsoventral axis which are critical in specifying the different cell types along the axis.

The rostrocaudal axis relies upon several layers of patterning and signals. The original inductive signals that produce the neural plate, mediated by BMP and its inhibitors chordin, noggin, and follistatin appear sufficient to specify the rostral CNS and forebrain. The more posterior (caudal) portion of the neuraxis utilizes the fibroblast growth factor (FGF) family of proteins and the steroidlike retinoic acid to pattern the midbrain, hindbrain, and spinal cord. There are eight segments of the hindbrain called rhombomeres. Rhombomeres one through five comprise the metencephalon, while rhombomeres six through eight comprise the myelencephalon. HOX genes are expressed in rhombomeres three through eight and are regulated by retinoic acid.

Figure 11-1. Two stages in the development of the neural tube (only half of each cross-section is shown). A. Early B. Later.

To better understand the finer patterning of the neuraxis, the organization of the hindbrain serves as a model system. Within the hindbrain, discrete swellings called rhombomeres occur in a distinct pattern. The rhombomeres contain sensory and motor neurons that form the cranial nerves that leave the CNS to innervate specific target tissues that develop from the branchial arches, an evolutionary remnant from the gills of aquatic vertebrate ancestors. For example, rhombomeres 4 and 5 contain the neurons/nuclei that give rise to the facial nerve (cranial nerve VII) which go on to innervate the muscles of facial expression that develop from the second branchial arch. The Hox family of transcription factors demonstrates a very specific pattern of expression within the hindbrain rhombomeres. This family of genes is clustered on the chromosomal DNA, with the genes in the 5' end of the cluster preferentially expressed in the more caudal portions of the neural tube. Conversely, the rostral rhombomeres contain the hox gene products from the 3' end. Thus, each rhombomere is defined by a certain combination of Hox gene products. These transcription factors delineate the identity of the neurons within each rhombomere— for example, Hoxb-1 is highly expressed in rhombomere 4 which gives rise to facial neurons. Elimination of this gene results in the development of trigeminal neurons instead of facial neurons in rhombomere 4. Other genes influence the expression of the hox genes, like Krox-20, which are themselves subject to other inducing factors. In this way, CNS development is built upon layers of specific, regulated signaling between cells that orchestrate a symphony of gene activation and inhibition resulting in precise cell type identity.

This precise system is reiterated throughout embryonic development in many organ systems and tissues. Because the nervous system is the most structurally and functionally complex organ system, it is also the most susceptible to perturbation and damage. A number of internal (genetic mutations) and external (teratogens) can upset the development of this system, with maternal alcohol exposure being a prime example.

COMPREHENSION QUESTIONS

[11.1] A 54-year-old man presents to your clinic with a 1-year history of progressively worsening gait disturbance. Additionally, he has recently begun to have some slurred speech. After extensive workup and testing, you diagnose him with a sporadic form of cerebellar ataxia. From what embryologic structure does the cerebellum arise?

A. Telecephalon

B. Mesencephalon

C. Metencephalon

D. Myelencephalon

[11.2] You are following a 44-year-old man who was recently diagnosed with amyotrophic lateral sclerosis (ALS) after presenting with difficulty writing secondary to hand and finger weakness. ALS is a disease of the anterior horn cells (motor neurons of the spinal cord). From what part of the neural tube did the cells affecting this man’s writing arise?

A. Ventral aspect of the cranial two-thirds of the neural tube

B. Dorsal aspect of the cranial two-thirds of the neural tube

C. Ventral aspect of the caudal one-third of the neural tube

D. Dorsal aspect of the caudal one-third of the neural tube

[11.3] A 24-year-old woman with severe nodulocystic acne presents to your clinic and is interested in beginning therapy with isotretinoin (Accutane) which is a derivative of retinoic acid. You agree to prescribe the medication after administering a pregnancy test which is negative. In order for her to get the medication, however, you require that she also takes birth control and uses at least one other form of contraception because Accutane is a known teratogenic agent, interfering with the action of endogenous retinoic acid. Endogenous retinoic acid is important for what stage of differentiation of the developing CNS?

A. Formation of the neural plate

B. Fusion of the neural groove to form the neural tube

C. Craino-caudal axis differentiation of the neural tube

D. Dorsoventral axis differentiation of the neural tube

Answers

[11.1] C. The cerebellum arises from the metencephalon. The cranial twothirds of the neural tube (which develops into the brain) is divided into five dilations along its craino-caudal axis. From cranial to caudal they are the telencephalon, which becomes the cerebral hemispheres; the diencephalon which becomes the thalamus, hypothalamus, epithalamus, and subthalamus; the mesencephalon which becomes the midbrain; the metencephalon which becomes the pons and cerebellum; and the myelencephalon, which becomes the medulla. The one-third of the neural tube caudal to these dilatations becomes the spinal cord.

[11.2] C. ALS is a disease that affects the motor neurons in the spinal cord which arise from the ventral aspect of the caudal one-third of the neural tube. Recall that the cranial two-thirds of the neural tube differentiate into the brain and brainstem, and the caudal one-third becomes the spinal cord. Also recall that the dorsal aspect of the neural tube becomes sensory neurons while the ventral aspect becomes motor neurons. Therefore, motor neurons in the spinal cord (those controlling the hands and fingers) would have arisen from the ventral aspect of the caudal one-third of the neural tube.

[11.3] C. Retinoic acid is an important signaling molecule involved in the cranio-caudal differentiation of the neural tube. A gradient of retinoic acid is established, with higher concentrations at the cranial end of the neural tube. Maternal ingestion of Accutane results in higher than normal concentrations of retinoic acid and disrupts this gradient, resulting in birth defects and spontaneous abortions. Accutane is FDA pregnancy category X.

NEUROSCIENCE PEARLS ❖ The CNS develops through a series of regulated spatial and temporal signals that pattern and differentiate primitive ectoderm into the CNS. ❖ Structurally, the CNS begins as a flat plate that progressively folds into a tube and elongates, with dilated regions corresponding to specialized structures, for example, cerebral cortices. ❖ CNS development is very sensitive to perturbation and is susceptible to numerous exogenous toxins and teratogens.

REFERENCES

Calhoun F, Warren K. Fetal alcohol syndrome: historical perspectives. Neurosci Biobehav Rev. 2007;31(2):168–71. Review. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 1991. 

Sadler TW, eds. Langman’s Medical Embryology. 7th ed. Baltimore, MD: Williams and Wilkins; 1995.

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