Neurodevelopment

Mon, June 20th

How Does the Nervous System Develop?

Neural crest specification: migrating into genomics. Laura S. Gammill & Marianne Bronner-FraserNature Reviews Neuroscience 4, 795-805 (October 2003)

Nervous System Beginnings

• Embryos are initially made of a single sheet of cells.

• This cell layer undergoes gastrulation, an inward folding that produces 3 cell layers:– Ectoderm (outside)

– Mesoderm (middle)

– Endoderm (inside)

The Notocord

• Gastrulation forms the notocord (a tube of mesoderm cells).

• Above the notocord lies the ectoderm that gives rise to the nervous system (neuroectoderm)

• The notochord also sends signals to make certain neuroectodermal cells become neural precursor cells, a process called neurulation.

Neurulation

• BMP, Wnt, retinoic acid, Sonic Hedgehog, and FGF are all important signaling molecules for neurulation.

• The neuroectoderm cells exposed to these signals thicken into the neural plate on approx. day 16 of development.

Nervous System Formation

• The neural plate folds inward to create the neural tube on approx. day 21. This is the basis for the brain & spinal cord.

• Some of the neural precursors will create neuroblasts; these are the basis for neurons.

Neural Tube

Neural Crest

• The cells at the dorsal (“top”) part of the neural tube are called the neural crest cells.

• These cells form the basis for sensory relay neurons to the thalamus.

• At the ventral (“bottom”) portion is the floorplate. These cells form primary motor neurons sent to the muscles.

But How Do These Cells Know What to Become?

• BMP and Wnt chemical signals are expressed at high levels at the dorsal neural crest cells.

• Sonic Hedgehog (Shh) is expressed in high levels at the ventral region (floorplate).

• These chemicals form a concentration gradient from high to low.

From Lecture by Pete Wenner, Emory University , 2007

Dorsoventral Patterning

• The amount of the chemicals that a cell is exposed to influences how it develops.

• The effects of this concentration gradient on development is called dorsoventral patterning.

From Lecture by Pete Wenner, Emory University , 2007

Summary• Gastrulation creates an inward folding of cells to create three

layers, and forms the notocord.• Above the notocord, neuroectoderm cells give rise to the

nervous system.• In neurulation, chemical signals from the notochord make

certain neuroectodermal cells become neural precursor cells.• These neural precursor cells thicken into the neural plate.• The neural plate folds inward to create the neural tube (brain &

spinal cord).• Neuroblasts will continue to become neurons.• The dorsal end of the neural tube contains neural crest cells.• The ventral end of the neural tube contains the floorplate.• High levels of BMP and Wnt signals at the neural crest influence

the development of sensory cells.• High levels of Sonic hedgehog signals at the floorplate

influence the development of motor neurons.• This concentration gradient of BMP, Wnt, and Shh and its

effects on development is called dorsoventral patterning.

The Formation of Brain Subdivisions

http://faculty.washington.edu/chudler/dev.html

How Does the Brain Form?

• The rostral (“front”) part of the neural tube undergoes several folds and changes to shape it into:– Prosencephalon

(Forebrain)– Mesencephalon

(Midbrain)– Rhombencephalon

(Hindbrain)

Neuroscience. 2nd edition.Purves D, Augustine GJ, Fitzpatrick D, et al., editors.

Sunderland (MA): Sinauer Associates; 2001.

Prosencephalon

• Telencephalon– Cerebral Cortex– Hippocampus– Basal Ganglia

• Diencephalon– Thalamus– Hypothalamus– Optic Cups

Mesencephalon

• Superior Colliculus

• Inferior Colliculus

• Midbrain Tegmentum

Mesencephalon

Future cerebral aqueduct

Rhombencephalon

• Metencephalon– Cerebellum– Pons

• Myencelencephalon– Medulla

And How Do These Regions Know What to Become?

• Once again, a concentration gradient.

• This time, it’s a gradient of FGF and Retinoic acid, which affect the expression of homeobox (Hox) transcription factors.

• This is known as rostrocaudal patterning.

http://faculty.pnc.edu/pwilkin/homeobox.html

What If Things Go Wrong?

• Changing the expression of even just one homeobox transcription factor can have a huge effect!

Matsuo et al, 1995

Summary• The rostral neural tube forms the basis for the brain’s

subdivisions.• Prosencephalon (Forebrain)

– Telencephalon• Cerebral Cortex, Hippocampus, & Basal Ganglia

– Diencephalon• Thalamus & Hypothalamus, Optic Cups

• Mesencephalon (Midbrain)– Superior & Inferior Colliculi, Midbrain Tegmentum

• Rhombencephalon (Hindbrain)– Metencephalon

• Cerebellum & Pons– Myelencephalon

• Medulla

• A concentration gradient of FGF and Retinoic acid help direct the development of these subdivisions.

• This gradient affect the expression of homeobox (Hox) transcription factors, and the process is known as rostrocaudal patterning.

• Changes in even one Hox transcription factor can have devastating results.

Developmental Disorders

http://embryology.med.unsw.edu.au/

Anencephaly

• Absence of a large portion of the scalp, skull, and brain, particularly the frontal cortex

• Often do not survive birth

• Are blind, deaf,unconscious,and unable tofeel pain

Holoprosencephaly

• Severe skull and facial deformities that often result in death before birth

• Severity depends on degree of malformation

• May also experience seizures & language, vision, or hearing problems

Griffiths, Paul D., Variend, Dick, Evans, Margaret, Jones, Angharad, Wilkinson, Iain D., Paley, Martyn N. J., Whitby, Elspeth. Postmortem MR Imaging of the Fetal and Stillborn Central Nervous System. AJNR Am J Neuroradiol 2003 24: 22-27

Hydrocephalus

• Symptoms:– Increased head size & downward gaze– Seizures– Separation of bones of the skull– Abnormal Reflexes

http://www.seattlechildrens.org/medical-conditions/chromosomal-genetic-conditions/hydrocephalus/

Spina Bifida

• Associated with orthopedic deformities, and sometimes below-average intelligence, depression, and gastrointestinal difficulties

• “Split spine”

Rett Syndrome

• Characterized by deficits in “learning, speech, sensory sensations, mood, movement, breathing, cardiac function, and even chewing, swallowing, and digestion”

• May also include seizures• More common in females

From RettSyndrome.org

Tourette’s & Tic Disorders

• Repeated vocal & motor tics (involuntary movements or vocalizations)

• More common in males• Extremely high co-morbidity with

other developmental disorders

• Likely inherited

From tsa-usa.org

Autism Spectrum Disorder• Significant Impairments in social

interactions and verbal & non-verbal communication– Restricted patterns of behavior, interest, and

activities• Repetitive behaviors & insistence on

routine• May also exhibit sensory problems or

sensitivity• Symptoms usually develop before 3

years of age

Asperger’s Syndrome

• Specific type of Autism Spectrum Disorder– Show significant social

impairments

– Restricted and repetitive stereotyped behaviors

– May be clumsy

– Often quite verbal & usually very intelligent

• Affects about 1 to 36 persons per 10,000 people

http://static.open.salon.com/files/dustin_hoffman_rain_man1218236383.jpg

Fetal Alcohol Syndrome

• Intellectual and learning disabilities

• Attention deficits & hyperactivity

• Delayed language

• Coordination deficits

• Sensory problems

Wattendorf, D. J. and M. Muenke (2005). "Fetal alcohol spectrum disorders." American family physician 72(2): 279-282, 285.

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