Lecture 1 - Development of the Brain - Part I - 2025 - Case Western

Case Western Reserve University School of Dental Medicine Facial Growth - HEWB 123 DEVELOPMENT OF THE BRAIN Part I Karla Coburn, Ph.D. [email protected] Class Outline 1. Basics of the Nervous System: ✓ Division ✓ Types of cells...

Case Western Reserve University School of Dental Medicine Facial Growth - HEWB 123 DEVELOPMENT OF THE BRAIN Part I Karla Coburn, Ph.D. [email protected] Class Outline 1. Basics of the Nervous System: ✓ Division ✓ Types of cells ✓ Anatomy 2. Early embryonic development: ✓ Gastrulation ✓ Somitogenesis ✓ Neural induction/neurulation ✓ Neural crest cells ✓ Neural tube defects 3. Development of the Brain Vesicles ✓ Development of the Primary Brain Vesicles ✓ Development of the Secondary Brain Vesicles Nervous System Overview Enclosed by meninges: ✓ Dura Mater ✓ Cranial nerves ✓ Leptomeninges ✓ Spinal nerves Arachnoid ✓ Sensory ganglia Cell body of ✓ Autonomic ganglia neurons Pia Mater Smooth muscle, cardiac muscle and glandular epithelium. Gray Mater White Mater Thoraco-Lumbar Cranio-Sacral - Cell body of neurons - Axons (tracts) T1 – L2/3 - Cranial nerves III, VII, IX, X (within nuclei) - Glia cells - S2-S4 Pelvic splanchnic nn - Glia cells  Cells of the Nervous System Neurons: main cells of the NS, cell bodies are located within gray matter of CNS and within ganglia of PNS Glial Cells CNS: – Astrocytes – Oligodendrocytes Gray matter – Ependymal cells – Microglia – Radial Glia cells (embryonic) Neurons PNS: – Schwann cells (PNS) – Satellite cells (PNS) White matter Types of Neurons (Morphological classification) Types of Neurons (Functional classification)  The Spinal Cord A= ventral horn (Anterior gray column) Sensory neurons (pseudounipolar) B= dorsal horn (Posterior gray column) C= central canal dura mater DORSAL D= ventral groove dorsal root Motor neurons are located in the ventral White mater horn, while sensory neurons are located B outside the spinal C cord, inside dorsal Interneuron root ganglia Gray mater Motor A Sensory neuron neuron (pseudounipolar) Dorsal root ganglion Spinal D nerve VENTRAL ventral root Autonomic Nervous System Dorsal Functional components Somatic Afferent skin, muscle, tendon, joint capsule SA Visceral Afferent smooth muscle, glands VA Sulcus Lateral horn Visceral Efferent Limitans VE autonomic ganglia Somatic Efferent SE skeletal muscle SA, VA, and SE run the full length of the cord. VE runs thru T1 – L2/3 (Sympathetic) Ventral S2 – S4 (Parasympathetic) Autonomic Nervous System ✓ The Autonomic Nervous System includes two efferent neurons arranged in series. The first neuron (preganglionic neuron) is located inside the CNS. It emerges from the CNS and synapses with a second neuron (postganglionic neuron), located outside the CNS, in an autonomic ganglion. Parasympathetic system Autonomic Nervous System The Brain Septum Fornix pellucidum Forebrain (Prosencephalon) Corpus Cerebrum Telencephalon Callosum Cerebral cortex basal ganglia (subcortical nuclei) coordination of voluntary movements Diencephalon Thalamus Hypothalamus Epithalamus Midbrain (Mesencephalon) Colliculi (visual & auditory processing) Thalamus Hindbrain (Rhombencephalon) Hypothalamus Metencephalon Midbrain Cerebellum Pons (neuron pathways) Pons Cerebellum (motor control) Brainstem Myelencephalon Medulla Oblongata Medulla (many autonomic functions) Ventricles of the Brain Superior Sagittal sinus (Dural venous sinus) Lateral Spaces in brain filled with cerebro-spinal fluid (CSF) (light blue) Interventricular Arachnoid foramina of Moro granulations Lateral (right & left) 3rd 4th note passageways connecting internal brain vesicles and subarachnoid space surrounding brain and spinal cord 3rd communications between CSF-filled spaces (light blue) communicates with blood-filled Cerebral Aqueduct dural venous sinuses (purple) through (Sylvius) arachnoid granulations 4th Central canal  CN I Cranial Nerves CN II ✓ 12 pairs: motor, sensory or mixed ✓ Most arise from the brainstem: except CN III CN I and II CN IV ✓ Motor: nuclei of motor neurons are CN V located in the brain CN VII CN VI ✓ Sensory: neurons located outside the CN VIII brain, in sensory ganglia CN IX ✓ Parasympathetic fibers are carried along with some cranial nerves: CN XII CN X III – VII – IX – X CN XI “Some Say Marry Money But My Brother Says Big Brains Matter More” I II III IV V VI VII VIII IX X XI XII Class Outline 1. Basics of the Nervous System: ✓ Division ✓ Types of cells ✓ Anatomy 2. Early embryonic development: ✓ Gastrulation ✓ Somitogenesis ✓ Neural induction/neurulation ✓ Neural crest cells ✓ Neural tube defects 3. Development of the Brain Vesicles ✓ Development of the Primary Brain Vesicles ✓ Development of the Secondary Brain Vesicles Gastrulation Oropharyngeal membrane Primitive Node  The primitive streak doesn’t reach the most anterior region of the embryo. Why? ✓ The formation and anterior extension of the primitive streak is induced by Wnt3 and brachyury. ✓ These molecules prevent head formation, so they must be inhibited on the future head region ✓ On the future head territory there is a signaling center called Anterior Visceral Endoderm (AVE), that blocks Wnt3 and brachyury, preventing cranial expansion of the primitive streak and securing the territory of head formation Gastrulation and Cell Fates Oropharyngeal Membrane Early Primitive Streak stage Prechordal Plate ✓ After the displacement of the hypoblastic cells, a second wave of Path of migration cells ingress through the primitive streak and move anteriorly towards the oropharyngeal membrane, forming the prechordal plate  Prechordal Plate ✓ The prechordal plate (also called prechordal mesoderm) is rostral to the notochord, posterior to the oropharyngeal membrane and AVE and beneath the developing forebrain. ✓ The prechordal plate and Anterior Visceral Endoderm are early signaling centers that induce the development of the brain The Notochord ✓ The epiblast cells that migrate through the node, along the embryo’s midline, toward the oropharyngeal membrane give rise to the notochord, which: Forms a midline axis, which will serve as the basis of the axial skeleton Induces the formation and folding of the neural plate Contributes to the dorso-ventral patterning of the neural tube. After Gastrulation ✓ Following Gastrulation, remaining epiblast constitutes the Definitive Ectoderm, which differentiates into: 1. Surface Ectoderm 2. Neural Plate 3. Neural Crest cells 4. Ectodermal Placodes: Olfactory, nasal, lens, otic and epipharyngeal placodes: (assist neural crest cells to form sensory ganglia for nerves of Neural crest the pharyngeal arches: V – VII – IX – X Surface ectoderm  The Neural Induction ✓ The notochord secretes Bone Morphogenetic Protein (BMP) antagonists such as Chordin, Noggin, Follistatin and Nodal, which block BMP signaling in the undifferentiated ectoderm. Without such inhibition, BMPs would induce an epidermic fate. BMP block allows neural tissue to form. Ectoderm Source of BMP4,7 → epidermal fate Mesoderm Source of BMP inhibitors → neural fate Endoderm Cranial ectoderm Surface Placodes Neural Neural plate Neural Placodes Surface ectoderm crest crest ectoderm Neurulation ✓3rd week: neurogenic factors released by the notochord induce the overlying ectoderm to form the neural plate (neuroectoderm), which folds to form the neural tube. Shh and anti-BMPs Paraxial mesoderm Neural crest cells undergo an epithelial- mesenchymal transformation and delaminate from neural plate Neural tube is formed and detaches from surface ectoderm Neural Crest and derivatives ✓ Neural Crest Cells are migratory, pluripotent cells that contribute to a vast diversity of structures, especially in the head and neck 1) Neural derivatives (neurons of): ✓Sensory ganglia of spinal nerves (dorsal root ganglia) ✓Sensory ganglia of cranial nerves (V, VII, VIII, IX, and X) ✓Sympathetic ganglia (paravertebral and Preaortic ganglia) ✓Parasympathetic ganglia of cranial nerves III, VII, IX, and X ✓Parasympathetic ganglia associated with the gut tube ✓Adrenal medulla (chromaffin cells) 2. Neural Crest Cells: Non-neural derivatives ✓ Glia cells of PNS: Schwann cells and satellite cells ✓ Melanocytes ✓ Odontoblasts and cementoblasts ✓ Skeletal components derived from the pharyngeal arches (cartilages and bones) ✓ Ciliary and pupillary muscles ✓ Leptomeninges: arachnoid & pia mater The migration of the neural crest cells is guided by signals from non- neuronal tissue, such as somites. Somitogenesis ✓ Neurulation occurs concomitantly uncondensed with Somitogenesis paraxial mesoderm ✓ Cells that migrate more posteriorly through the node and cranialmost condensing part of the primitive streak form paraxial mesoderm the paraxial mesoderm ✓ As neurulation is occurring, paraxial mesodermal cells begin Somitomeres (partially to coalesce and forming condensed) → further compaction occurs condensed segments: somites. Somites: form at the 20 th day, in a cranial-caudal sequence) The paraxial mesoderm in the future head region of the embryo remains unsegmented and becomes dispersed, Somites: form at the 20th forming the head mesenchyme (along with neural crest day, in a cranial-caudal cells contribution). sequence) Somitogenesis Fate of the Somite Vertebral After paraxial mesoderm condenses as a somite, it segments to form: arch Dermomyotome dermatome: dermis myotome: muscles Sclerotome (forms vertebrae and IVD) Spinal cord Somites release molecules that contribute to the neural tube patterning (RA, AP patterning), give rise to most of the axial skeleton, including the vertebral column and part of the occipital bone of the skull; to the voluntary musculature of the neck, body Dorsal root wall, and limbs; and to the dermis of the body. ganglion Body of vertebra Notochord: Nucleus pulposus of the IVD Fate of the Somite Vertebral After paraxial mesoderm condenses as a somite, it segments to form: arch Dermomyotome dermatome: dermis myotome: muscles Sclerotome (forms vertebrae and IVD) Spinal cord Somites release molecules that contribute to the neural tube patterning (RA, AP patterning), give rise to most of the axial skeleton, including the vertebral column and part of the occipital bone of the skull; to the voluntary musculature of the neck, body Dorsal root wall, and limbs; and to the dermis of the body. ganglion Body of vertebra Notochord: Nucleus pulposus of the IVD By Jmarchn - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=95036158 Neural Plate Formation and Neurulation Day 22: Neural tube begins folding and fuse in the occipito-cervical region, forming cranial neuropore and caudal neuropore Neural fold Pericardial bulge Otic placode Somite Neural Plate Formation and Neurulation Closure of Cranial (Anterior) Neuropore Closure of Caudal (Posterior) Neuropore Neural Tube Defects ✓ NTDs comprise a diverse set of birth defects that are usually considered to arise during the third and fourth weeks post-fertilization, involving the neural tube and/or associated structures. ✓ Neural Tube Defects result mostly of failure of the neural tube or neuropores to close properly, resulting in phenotypes that range from trivial to fatal. Spinal cord/caudal neuropore: spina bifida Cranial neuropore: anencephaly (meroencephaly) Prevalence of NTD in US: 1/1,500 ✓ Causes: folic acid deficiency, genetic predisposition, teratogens. Other factors: obesity, smoking, hyperthermia. ✓ Fetal Diagnosis: high levels of alpha-fetoprotein in amniotic fluid Spinal cord Cervical spina bifida Spina bifida with Spina bifida with Spina bifida occulta myelomeningocele rachischisis Neural Tube Defects: Anencephaly ✓ Cranial neuropore fails to close. ✓ Neural tissue is disorganized and is exposed to amniotic fluid, which causes necrosis and loss of tissue. ✓ Forebrain, midbrain, and most of the hindbrain and calvaria are absent. ✓ This defect is always fatal 1:10,000 live births. Fetus with anencephaly and craniorachischisis. The neural tube has failed to close in cranial and upper spinal cord Fetus and baby with anencephaly (absent brain) due to a lack of closure of the cranial neuropore. regions resulting in massive necrosis of neural tissue. Skull defects and encephaloceles (cranium bifidum) ✓ Ossification defects in bones of the skull (associated or not to NT defects) can result in meningoceles, encephalomeningoceles and encephalomeningohydroceles ✓ The most frequently affected bone is the squamous part of the occipital bone ✓ Severity of the herniation depends on the size of the bony defect Meningocele Encephalomeningocele Encephalomeningohydrocele Class Outline 1. Basics of the Nervous System: ✓ Division ✓ Types of cells ✓ Anatomy 2. Early embryonic development: ✓ Gastrulation ✓ Somitogenesis ✓ Neural induction/neurulation ✓ Neural crest cells ✓ Neural tube defects 3. Development of the Brain Vesicles ✓ Development of the Primary Brain Vesicles ✓ Development of the Secondary Brain Vesicles Development of the Primary Brain Vesicles Following neural induction, the cephalic end of the neural tube shows three dilations: Prosencephalon Mesencephalon Rhombencephalon 4th week Development of the Secondary Brain Vesicles By 5 weeks of development, the primary brain vesicles have differentiated into five secondary vesicles. LAT LAT Prosencephalon Telencephalon cerebral cortex 3rd basal ganglia Diencephalon thalamus Mesencephalon hypothalamus Aqueduct Cerebral Epithalamus Mesencephalon Mesencephalon Rhombencephalon Metencephalon 4th pons cerebellum Myelencephalon medulla Lamina terminalis: site of 4th week cranial neuropore closure 5th week Development of the Secondary Brain Vesicles ✓ The lumen of the developing spinal cord is continuous with that of the brain vesicles. They become filled with CSF, produced by choroid plexus LAT LAT ✓ Telencephalon → Lateral ventricles (2) ✓ Diencephalon → Third ventricle ✓ Midbrain → Cerebral aqueduct of Sylvius 3rd ✓ Hindbrain → Fourth ventricle Aqueduct Cerebral LATERAL 3RD AQUEDUCT 4th 4TH 5th week Hydrocephalus Accumulation of CSF in brain ~1-2/1000 newborns Enlarges vesicles Commonly due to Aqueduct blockage Treatment by shunts (usu. to peritoneal cavity) Summary