1. Early brain development
Domina Petric, MD

2. Developmental forces NATURE SELF-ORGANISATION NURTURE
Leonard E. White, PhD, Duke University

3. GENETIC SPECIFICATION SENSORIMOTOR EXPERIENCE
Developmental forces
GENETIC SPECIFICATION
DYNAMICAL SYSTEMS
SENSORIMOTOR EXPERIENCE
Leonard E. White, PhD, Duke University

4. Nature (lineage-derived signals) is expressed via gene transcription.
Developmental forces
Nature (lineage-derived signals) is expressed via gene transcription.
Nurture (environmental interactions) is experience dependent modulation of activity.
Self-organisation (cell-cell interactions) is mediated via activity-based mechanisms.
Leonard E. White, PhD, Duke University

5. Gastrulation
Gastrulation is an invagination of the developing embryo at the stage of the BLASTULA.
Gastrulation produces three principal germ layers:
ECTODERM (the outermost layer)
MESODERM (the middle layer)
ENDODERM (the innermost layer)
NOTOCHORD is derived from the MESODERM. Notochord is responsible for sending out chemical signals that interact with ECTODERM: that part of the ectoderm becomes the NEURAL PLATE. Notochord is important for inducing the differentiation from the neural plate.
Leonard E. White, PhD, Duke University

6. Wikipedia.org
Leonard E. White, PhD, Duke University

7. Gastrulation NOTOCHORD NEURAL PLATE ECTODERM MESODERM ENDODERM
Leonard E. White, PhD, Duke University

8. Neurulation Neurulation is initial formation of the nervous system.
The neural plate begins to rise up in its lateral margins and begins to close up to form a NEURAL TUBE.
Closing of the neural tube begins in the center of the neural plate and extends in anterior and posterior direction.
In the fourth week of embryonic life there is anterior and posterior end of the neural tube.
Anterior end is going to be BRAIN.
Rest of the neural tube (posterior part) will be SPINAL CORD.
Leonard E. White, PhD, Duke University

9. Study.com Neural tube Cephalic flexure Cervical flexure
Leonard E. White, PhD, Duke University

10. Neural tube PROSENCEPHALON RHOMBENCEPHALON https://www.uoguelph.ca
Diencephalon
will divide into
THALAMUS and
HYPOTHALAMUS
Neural tube
Metencephalon will form the PONS and entire
CEREBELLUM. Myelencephalon will form the
MEDULLA OBLONGATA.
PONTINE FLEXURE divides
into metencephalon and
myelencephalon.
RHOMBENCEPHALON
Leonard E. White, PhD, Duke University

11. Neural tube development overview
Embryonic brain
Adult brain derivates
Associated ventricular space
Prosencephalon (forebrain)
Telencephalon
(forebrain)
Cerebral cortex; basal ganglia, hippocampus, olfactory bulb, basal forebrain
Lateral ventricles
Diencephalon
Dorsal thalamus; hypothalamus
Third ventricle
Mesencephalon
Midbrain (superior and inferior colliculi)
Cerebral aqueduct
Rhombencephalon (hindbrain)
Metencephalon
Cerebellum, pons
Fourth ventricle
Myelencephalon
Medulla oblongata
Spinal cord
Central canal
Leonard E. White, PhD, Duke University

12. Inductive signals
Floor plate of the neural plate (just above the notochord) is very important because it gives inductive signals for the ventral parts of the neural tube.
Floor plate itself recieves inductive signals from the notochord.
Roof plate also responds on the notochord´s inductive signals and it is on the dorsal side of the neural tube.
Roof plate gives inductive signals for the dorsal parts of the neural tube.
Neural crest is a source of many different cells derived from it that migrate away from the neural crest.
These neural crest cells are exposed to differentiating signals and become neuronal and non-neuronal structures.
Leonard E. White, PhD, Duke University

13. Inductive signals
Floor plate will give rise to inductive signals that establish motor circuits and alfa motor neurons.
Roof plate will give rise to inductive signals that establish a dorsal identity of the developing walls of the neural tube: somatic sensory neurons (somatosensory neurons).
Leonard E. White, PhD, Duke University

14. Neural crest cells sensory neurons adrenergic neurons
cholinergic neurons
chromaffin cells
melanocytes
Leonard E. White, PhD, Duke University

15. Inductive signaling
It is the ability of a cell or a tissue to influence the fate of nearby cells during development by the synthesis in secretion of chemical signals.
These chemical signals are either steroid hormones or peptide hormones.
The precise timing of the expression of these inductive signals is crucial for the proper formation of the developing brain.
Leonard E. White, PhD, Duke University

16. Inductive signaling
Retinoic acid (metabolised from vitamin A) is a very important inductive signal (importance of vitamin A in early brain development).
Retinoic acid can translocate through cellular membranes and it can bind to a receptor within the cell.
That intracellular receptor becomes a transcription factor that is translocated to the nucleus and interacts with other binding proteins so it turns on particular genes.
Excess retinoic acid in developing embryo can be extremely harmful and becomes teratogen.
Leonard E. White, PhD, Duke University

17. Inductive signaling
Most of human brain inductive signals are PEPTIDE HORMONES.
Peptide hormones interact with surface bound receptors.
Bone morphogenetic protein (BMP) interacts with surface receptor SERINE KINASE that phosphorilates transcriptional regulator SMAD.
Activated SMAD associates with additional helper proteins and this complex is translocated into the nucleus where it acts as transcription regulator.
BMP signaling is very important in mesodermal tissue: inducing of bone cells development.
BMP signaling in the ectodermal tissue induces the formation of epidermis.
Leonard E. White, PhD, Duke University

18. Inductive signaling
Factors NOGGIN and CHORDIN can antagonise the interaction of BMP with its receptor.
When noggin and chordin antagonise the interaction of BMP with ectodermal receptors, that part of ectoderm will contine to develop in neural direction (neuroectoderm, neural plate).
Without noggin and chordin entire ectoderm would become SKIN.
Leonard E. White, PhD, Duke University

19. Inductive signaling
Sonic hedgehog (SHH) is protein hormone that interacts with receptors that are bound to the surface of the cell.
SHH receptor is a protein called PATCHED PROTEIN that interacts with SMOOTHENED PROTEIN.
Interaction bethween the patched and smoothened protein will activate a series of transcription factors.
Transcription factor GLI 1 becomes induced, binds to DNA and modulates gene expression.
SHH mediated signaling pathway is crucial for the proper closure of the neural tube.
Leonard E. White, PhD, Duke University

20. Inductive signaling coordination
Inductive signals are cooordinated both in location and developmental time.
Leonard E. White, PhD, Duke University

21. Homeotic (HOX) genes
There are four clusters of Hox genes: HoxA (chromosome 7), HoxB (chromosome 17), HoxC (chromosome 12) and HoxD (chromosome 2).
These Hox genes clusters are responsible for beginning to establish regional identity in the developing nervous system.
There is anterior to posterior pattern of expression of these clusters: development of brain and spinal cord segments.
Leonard E. White, PhD, Duke University

22. Proliferation
cells are produced every minute in the developing embryo.
The production of neurons is restricted in time to a very narrow period: SECOND TRIMESTER OF PREGNANCY.
Adult neurogenesis is mostly restricted to the hippocampus: learning and creation of new memories.
Precursor cell has a body and two processes that make contact with inner and outer surface of developing neural tube.
The outer neural tube surface will become the PIAL surface of the brain.
The inner surface is going to differentiate into the EPENDYMAL LINING of the ventricles in the human brain.
Leonard E. White, PhD, Duke University

23. Proliferation
Cell body of the precursor cell can migrate via its processes towards the pial and ependymal surface of the neural tube.
When the cell body migrates close to the pial surface, DNA starts to replicate.
When the cell body migrates then close to the ependymal surface, mitosis occurs.
Symmetrical division will produce two precursor cells.
Asymmetrical division produces two different types of cells: one is precursor (progenitor) cell and other is NEUROBLAST.
Neuroblast can then differentiate into the neurons and glial cells.
Leonard E. White, PhD, Duke University

24. Migration
The ventricular zone of the neural tube is where mitosis is happening.
The cortical plate is the first formation of the cerebral cortex.
Neuroblasts migrate from ventricular zone towards the cortical plate along the radial fiber formed by radial glial cells.
Leonard E. White, PhD, Duke University

25. Inside-out cortical development
The pyramidal neuron cells (excitatory, glutamate releasing neurons) that are born in the late first trimester of pregnancy will populate the inner and the outer margins of the cortical plate.
Cells that are born in the early second trimester of pregnancy will reside in the lower portion of the cortical plate that will differentiate into CORTICAL LAYER VI.
During the second trimester of pregnancy there is progression of cells from inner to outer layers of the cortical plate: from CORTICAL LAYER VI up to CORTICAL LAYER II.
Leonard E. White, PhD, Duke University

26. Inside-out cortical development: pyramidal neuron cells
CORTICAL LAYER 1
CORTICAL LAYER 2
CORTICAL LAYER 3
CORTICAL LAYER 4
CORTICAL LAYER 5
CORTICAL LAYER 6
WHITE MATTER
FIRST TRIMESTER
SECOND TRIMESTER
Leonard E. White, PhD, Duke University

27. Tangential migration
Most of the inhibitory interneurons of the cerebral cortex are derived from the developmental region that is deep in the base of the forebrain: GANGLIONIC EMINENCE.
Ganglionic eminence differentiates into lateral and medial ganglionic eminence (LGE, MGE).
From LGE and MGE neurons differentiate and migrate in radial and TANGENTIAL direction.
Tangential migration is important for inhibitory interneurons that migrate from LGE and MGE up into the cerebral cortex.
Ganglionic eminences also give rise to the basal forebrain structures: basal ganglia and some cells that are part of amygdala.
Leonard E. White, PhD, Duke University

28. Precursor cells differentiation mechanisms
LOCAL CELL-TO-CELL INTERACTIONS MEDIATED VIA SURFACE RECEPTORS: INDUCTIVE SIGNALING
CELL LINEAGE (TRANSCRIPTIONAL HISTORY OF A CELL)
Leonard E. White, PhD, Duke University

29. SUICIDE GENES APOPTOSIS
Death of brain cells (apoptosis) is important mechanism for establishing an appropriate complement of cells in the different gray matter structures in the CNS.
SUICIDE GENES
Leonard E. White, PhD, Duke University

30. Literature
neuroscience: Leonard E. White, PhD, Duke University
Study.com
Wikipedia.org
Leonard E. White, PhD, Duke University