Embryology, Central Nervous System


Article Author:
Mohamed Elshazzly


Article Editor:
Omar Caban


Editors In Chief:
Rodrigo Kuljis
Oleg Chernyshev
Aninda Acharya


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
10/27/2018 12:31:28 PM

Introduction

Central nervous system (CNS) embryology is a broad subject. This article serves as a summary of CNS organogenesis as well as a review the framework of embryology, the embryogenesis of the brain and spinal cord, various tests that can be performed in utero to test for CNS anomalies, and problems that may be encountered during embryogenesis, with particular attention to the CNS.

The CNS system involves 3 germinal layers: ectoderm, mesoderm, and endoderm.

  1. The ectoderm is the key initiating player in the embryogenesis of the CNS. The ectoderm is further sub-specialized as the (1) surface ectoderm, which differentiates into the epidermis, nails, and hair. The ectoderm is also sub-specialized to form the (2) neural ectoderm, which gives rise to the neural tube and neural crest, which subsequently give rise to the brain, spinal cord, and peripheral nerves.
  2. The endoderm gives rise to the lining of the gastrointestinal and respiratory systems. It also gives rise to abdominal organs such as the liver, pancreas, and bladder.

  3. The mesoderm is differentiated into 3 parts:

  • Paraxial mesoderm: This part of the mesoderm contains mostly somites which give rise to the axial skeleton, dermis, and muscle.
  • Intermediate mesoderm: This part of the mesoderm gives rise to the gonads, kidneys, and urogenital structures. 
  • Lateral plate mesoderm is further classified into parietal mesoderm and visceral mesoderm, which give rise to the limb skeleton and muscular wall of the gut tube, respectively.

Embryological Transformations

Because these changes do not occur at once, embryology is a complicated subject. The following timing of embryological developments, with particular attention to the CNS, offer a greater understanding of the process.

  • Weeks 1 to 3: Zygote formation, blastocyst, and gastrulation occur
  • Mid-fourth week: Embryo is linear and uniform; notochord formation occurs
  • Late-fourth week: Many forms of differential growth occur; upper limb buds always develop before the lower limb bud
  • Fifth week: Limb buds more pronounced
  • Sixth week: Can begin to see eyes and auricular hillocks, which will develop into the external ears
  • Seventh week: Formation of eyes, ears, and fingers
  • Late eighth week: Formation of all organ systems
  • Nine to 12 weeks (11 to 14 gestational age): Embryo has a large head, and small body and this is the time where the body grows in an attempt to catch up with the limbs. The genitalia can be recognized during this period giving a chance for parents to find out the gender of the embryo.
  • Thirteen to 16 weeks (15 to 18 gestational age): Coordinated limb developments and ossification of skull occur; Ovaries differentiate and contain primordial ovarian follicles that contain oogonia; the eyes face anteriorly, and ears are in place. 
  • Seventeen to 20 weeks (18 to 22 gestational ages): Eyebrows and head hair visible at 20 weeks
  • Twenty-one to 25 weeks (23 to 27 gestational age): Type II pneumocytes to secrete surfactant. It is after this stage when babies are considered viable.
  • Twenty-six to 29 weeks (28 to 31 gestational age): Eyelids open; quantity of white fat increases. The CNS has matured and can control breathing as well as temperature function. Additionally, the bone marrow takes over (from the yolk sac) as the major site of erythropoiesis.
  • Thirty to 34 weeks (32 to 36 gestational age): Maturation and growth of organs occur
  • Thirty-five to 38 weeks (37 to 40 gestational age): Baby now has a firm grasp with hands. Testes may have descended in males.

Development

Embryogenesis: Weeks 2 to 8

Beginning with the trilaminar germ disc, which refers to the epiblast and hypoblast, the epiblast cells undergo an epithelial-mesenchymal transition that replaces the hypoblast. They also proliferate in the middle layer to form the mesoderm where it will remain mesenchymal to form connective tissue. The primitive streak then starts to appear superiorly from the thickened region of ectoderm. It grows caudal to cranial and induces the notochord formation. The ectoderm then invaginates as cells migrate to form the primitive node and primitive pit where the notochordal process is formed.

  1. Primitive pit is a depression at the center of the primitive node, which is an opening in the notochordal canal.
  2. Neurulation refers to the folding of the neural plate. The neural plate folds, via induction from the notochord, into the neural tube, which then becomes the neuroectoderm, which finally forms the CNS, namely the brain and spinal cord; the brain from cranial two-thirds of the segment and spinal cord from caudal one-third of the segment)
  3. Neural Crest cells form dorsal root ganglia and connective tissue in the head and neck.
  4. Notochord:
  • Defines longitudinal axis
  • Forms parts of the intervertebral discs, and not the spinal cord or spine
  • Notochordal process formed on top of the primitive node
  • Elongation of the notochordal process occurs caudally and goes upward to cranial end

The CNS is derived from the neuroectoderm: notochord induces the formation of the neural plate (thickening of the ectodermal layer), which further differentiates to form neural folds with a neural groove in between, leading to the formation of the neural tube (via neurulation).

Spinal Cord

The spinal cord is formed from the neural plate, now contains 3 layers:[1]

  1. Ventricular layer that lines the central canal
  2. Mantle layer that contains neuronal bodies, which will eventually form the gray matter
  3. Marginal layer that contains axons, and will eventually form the white matter

While this article summarizes the embryological changes that occur within the CNS, the peripheral nervous system (PNS) is formed from neuroepithelial cells. These cells travel from the pia mater to the ventricular layer of the spinal cord, where they differentiate and migrate to form glioblasts (for example, support cells, Schwann cells), neurons, and ependymal cells. As this information is often tested on boards, that myelin sheath, a sheath composed of support cells, wraps around axons and insulate neurons to increase the speed of neuronal conduction.

  1. Myelination of peripheral axons occurs via the neurolemma, which comes from Schwann cells (which come from neural crest cells).
  2. Myelination of CNS axons occurs via oligodendrocytes, which are neuroepithelium derivatives.

Three membranous layers cover the whole CNS:

  1. Dura mater: derived from surrounding mesenchyme and is tough and durable.
  2. Arachnoid mater: derived from neural crest; forms as a single layer with Pia mater.
  3. Pia mater: derived from neural crest; intimately covers the CNS.

Brain

During brain formation, there are 3 primary brain vesicles that differentiate into 5 secondary brain vesicles. See image.

  1. Prosencephalon, which becomes the forebrain: This later develops into the cerebral hemispheres which contain structures underneath such as epithalamus, thalamus, and hypothalamus. This section of the brain is responsible for consciousness, sensorimotor transformation, and sensory integration.
  2. Mesencephalon, which becomes the midbrain: This part of the brain undergoes little structure reorganization compared to the spinal cord and other brain vesicles.
  3. Rhombencephalon, which becomes the hindbrain: This part can be further divided into 3 segments:
  1. Metencephalon: The dorsal growth of the cerebellum (integrates sensory information to fine-tune output)
  2. Caudal myelencephalon: Similar to the structure of the spinal cord with “closed” central canal of Medulla
  3. Rostral myelencephalon: “Open part” of medulla; cerebrospinal fluid (CNF) is produced via choroid plexus and leaks into the subarachnoid space.

Finally, the hypophysis gives rise to the pituitary gland, which has 2 origins. The posterior pituitary is an outgrowth of the hypothalamus, and, therefore, has a direct connection. On the other hand, the anterior pituitary is an ectodermal growth from the mouth. It depends on a dense capillary network and communicates with the brain via the vascular system.

Testing

  • Non-invasive testing can be performed at 10 weeks of gestation. This tests for cell-free DNA in plasma of pregnant women and helps identify certain anomalies or diseases.
  • Amniocentesis, which is usually performed between 14 and 20 weeks, is the sampling of the amniotic fluid to screen for fetal anomalies. This is a diagnostic test.
  • First-trimester testing looks for risk of trisomy 21, trisomy 18, trisomy 13, and other neural tube defects.
  • Alpha-fetoprotein (AFP) is a hormone that is elevated in amniotic fluid in anomalies of the CNS and ventral abdominal wall. It is decreased when the fetus has trisomy 21, trisomy 18, or other chromosomal defects.
  • Anatomy sonogram can be performed throughout pregnancy, but particularly between weeks 16 to 22 to estimate the fetal weight and gestational age using measurements from:
  1. Head circumference
  2. Biparietal diameter
  3. Femur length (from epiphysis to epiphysis)
  4. Abdominal circumference

Although beyond the scope of this article, there is also a Quad-screen test which can be performed in the second trimester. The components of this screening test include AFP, hCG, Estriol, and Inhibin-A.[2]

Pathophysiology

Embryogenesis can be complicated and result in mild or extreme defects (pathophysiological changes).

  • Teratogenesis is defined as any external factor that can influence the growth of the embryo. Embryos are highly susceptible and critical between weeks 3 and 8 because that is when organ systems develop.
  • Dysraphism is the failure of fusion between symmetric halves of an anatomical structure. These include, and are not limited to, spina bifida malformations.
  1. Spina bifida occulta occurs when the vertebral column fails to fuse, but other layers develop normally. It is the least severe form of dysraphism and usually affects the lumbosacral region (S1 to S2 most commonly). It can be associated with moles, angioma, lipoma, and abnormal hair growth in the area of abnormality.
  2. Spina bifida aperta occurs when there is incomplete fusion of skin with or without a cyst. The spinal cord is still covered by the arachnoid mater, thus preserving subarachnoid space and preventing leakage of the CSF.
  3. Spina bifida cystica is the most severe form of dysraphism. Patients may develop urinary or fecal incontinence. 80% of these lesions occur in the lumbosacral region.

Dysraphism in the cranium causes malformations analogous to spina bifida[3]:

  1. Encephalocele: Protrusion of the brain into the subarachnoid space. It can be associated with Chiari III malformation during part of the cerebellum protrudes, and the spinal cord gets twisted. This is commonly associated with cleft lip and palate.
  2. Anencephaly is where the cerebral cortex and thalamic structures are generally absent, but the cerebellum, brainstem, and spinal cord are present (but may be deformed). This can occur due to the failure of notochord signaling which is necessary for median hinge point formation or induction of neural crest cell maturation.
  3. Holoprosencephaly: Failure of features to form along the midline of the face. Features include single central incisor, cyclopia, or unpaired cerebral hemisphere.
  4. Craniorachischisis totalis is when the entire neural plate fails to fold, and CNS is open to the amniotic cavity. These are often associated with still-born fetuses.

Clinical Significance

Pathophysiological processes that can occur during embryogenesis are rare and do not occur very often, and when they do, the newborn is alive and not stillborn. However, the newborn may require certain surgeries to correct the craniofacial anomalies before significant damage occurs.[4] Furthermore, those babies born with spina bifida require further evaluation with ultrasound and surgical correction of the spinal cord to prevent herniation or other complications.

Clinically speaking, to avoid the abnormal embryological development, the mother should abstain from teratogens or any external factor that can influence the growth of the baby, especially during weeks 3 through 8 of the embryogenesis. Significant teratogens include alcohol, tobacco use, certain prescription drugs, and illicit drugs. Most importantly, women seeking to get pregnant or who are pregnant take multivitamins, especially folic acid supplements to aid with neurodevelopment.[5]


  • Image 6702 Not availableImage 6702 Not available
    Contributed by The Embryologic Perspective by Rice University (CC by 4.0 https://creativecommons.org/licenses/by/4.0/)
Attributed To: Contributed by The Embryologic Perspective by Rice University (CC by 4.0 https://creativecommons.org/licenses/by/4.0/)

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Embryology, Central Nervous System - Questions

Take a quiz of the questions on this article.

Take Quiz
Development of the spinal cord and vertebral column is dependent on which protein?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
The notochordal process formation starts with invagination of cells through which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following are not involved in the development of the midbrain and cerebellum?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is NOT true regarding early brain development?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Aside from the integumentary system, which other organ system develops out of the ectoderm?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which adult structures arise from the metencephalon?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which is the meninge that develops as a thin (last) layer that adheres directly to the spinal nerves?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the glial cell that makes myelin sheath in the central nervous system?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Embryology, Central Nervous System - References

References

van Gelder MM,de Jong-van den Berg LT,Roeleveld N, Drugs associated with teratogenic mechanisms. Part II: a literature review of the evidence on human risks. Human reproduction (Oxford, England). 2014 Jan     [PubMed]
Dorney E,Black KI, Preconception care. Australian journal of general practice. 2018 Jul     [PubMed]
Gouti M,Metzis V,Briscoe J, The route to spinal cord cell types: a tale of signals and switches. Trends in genetics : TIG. 2015 Jun     [PubMed]
Shamji MF,Ibrahim A, IMAGES IN CLINICAL MEDICINE. Cervical Meningocele. The New England journal of medicine. 2015 Jul 23     [PubMed]
Zakhary GM,Montes DM,Woerner JE,Notarianni C,Ghali GE, Surgical correction of craniosynostosis. A review of 100 cases. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2014 Dec     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Neurology. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Neurology, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Neurology, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Neurology. When it is time for the Neurology board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Neurology.