Chapter 16: Early Brain Development

Chapter 16: Early Brain Development

1. 1. First Three Steps

   • A. Primary Induction
     • DEF: setting up the body plan/organizing tissues and cells (identity)
     • a. Conception
       • Fertilization of egg by sperm
         • Blastula develops: (formation of hollow sphere of cells) (blastocel-internal region of blastula)
           • Fist like invagination is pushed into the Blastula
             • Forms Gastrula → sets up the 3 different tissue layers of the embryo
               • Ectoderm-outside Mesoderm- inside Endoderm- inside
                 • This region at the mouth of the Gastrula- is the blastopore (invagination of blastula) , cavity inside is called the archenteron
                 • During Gastrula: Signals of noggin to ectoderm → production of neuroectoderm
     • b. Formation of the Notochord
       • Notochord arises from mesoderm layer of gastrula
     • c. Mesoderm>ectoderm signaling = primary induction
     • d. Ectoderm> The neural plate>neural groove>neural tube. Neural crest, from the ridges of the neural groove
       • Top of neural groove give rise to the neural crest (large part of PNS)
         • Neural groove will pinched off, outside is ectoderm, makes neural tube
       • Spemann & Mangold experiment
         • Took region of dorsal lip of blastopore, implanted it in the ventral aspect of the second embryo
           • The transplant into host embryo can induce the formation of an extra body axis, creating conjoined twins.
             • Experiment found the "organizer" that accounted for the differentiation of gastrulation
     • e. Roofplate, floorplate, notochord, somites: sources of inductive signals
       • ROOFPLATE
         • Located the dorsal midline of the vertebrate neural tube. During early CNS development, the roof plate produces secreted factors, which control the specification and differentiation of dorsal neuronal cell types.
       • FLOORPLATE
         • Located at the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior ("head to tail") axis from the midbrain to the tail regions.
       • NOTOCHORD
         • The notochord lies along the anteroposterior and is composed of cells derived from the mesoderm. The notochord has been observed to have many functions including developmental functions. The most commonly cited functions are as a site of muscle attachment, vertebral precursor, and as a midline tissue that provides signals to the surrounding tissue during development.
       • SOMITES
         • Bilaterally paired blocks of paraxial mesoderm that form along the head-to-tail axis
     • Induction: The Molecular Basis
       • A. An Overview
         • (Secreted or cell surface) ligands bind receptors that signal to the nucleus and alter gene transcription
       • B. RA (Retinoic Acid) (1st example)
         • RA: Produced by the somites, roofplate, floorplate Membrane permeable
           • Binds to RA-Receptors (Intracellular receptors) Then complex migrates to the nucleus, binds to DNA etc. etc. alter transcription
       • C. BMPs (Bone Morphogenetic Proteins) (2nd example)
         • Secreted from roofplate/ somites
           • Bind to surface receptors serine kinase
             • Phosphorylation of SMAD proteins
               • Migration to nucleus---> bind DNA
         • D. BMPs elicit bone formation (osteogenesis) from ectoderm
           • This is prevented in the neural plate by noggin and chordin that bind to BMPs and prevent binding to receptor serine kinases
       • E.Shh (Sonic Hedgehog protein) (3rd example)
         • binds to 2 co-receptor proteins , patched + smoothen
           • Causes Gli1 to dissociate from an inhibitory complex
             • Gli1 migrate to nucleus , binds to DNA
       • F. These secreted factors specify expression of transcription factors. Basis of neuronal diversity
         • Overview: secreted factors --> Specify expression of transcription factors (alters transcription)
           • Proteins, regulate transcription (Cleaves, binds DNA)
             • Operate in combinatorial codes- specify neuronal types
       • G. Inductive interactions vs lineage
         • Inductive signals are key to vertebrate brain development
           • Lineage relationships are more important signals
     • f. Neural precursor cells: progenitor cells of neural tube/stem cells
     • g.Neuroblasts: postmitotic/not dividing/differentiate into neurons

2. Step Two: Proliferation : Neurogenesis

   • A. Massive numbers
     • Large numbers of neurons more glia! (86 billion)
       • 1st month of development
         • 250,000 neurons/minute
   • B. 2 classes of precursor cells
     • Symmetric Divisions
       • Slowly
         • Two new stem cells
           • Somatic Stem Cells
             • Many cell types but limited to tissue of origin
           • Embryonic Stem Cells
             • Any class of cell type (no limits)
           • Induced pluripotent stem cells (ipscs)
             • Fibroblasts: reprogram them with combinations of transcription factors
           • Both types of Stem Cells are self-renewing
     • Asymetric Divisions
       • neuroblasts and stem cells
         • Rapidly
           • 1 stem cell and one neuroblast
   • C. Neuroblasts
     • Differentiate into neurons and are postmitotic
       • They have “birthdates” = time of final DNA synthesis
         • G1--> DNA synthesis --> G2 --> mitosis --> G1
           • Determine Time of Birthdate
             • Injedct 3H-D or bromo-deoxy-uridine (BrdU)
               • e.g. mouse at E 12, inject mom with BrdU
                 • Look in adults → see labeled cells , they were born at ER
   • D. Proliferation Location
     • Occurs in the germinal zone adjacent to central canal and ventricles.
   • E. Neurogenesis generally precedes gliogenesis.
     • Figure 22.10 Mechanisms that guide neuronal and glial differentiation in neural ectoderm

3. Step 3: Migration: Programming Differentiation

   • A. Often Long distances: Because the embryo is quite small
   • B. Importance
     • 1) brings neurons into different inductive environments;
     • 2) Enables synaptic connections (sets up formation of appropriate neuronal connections)
   • C. CNS
     • 1. Cerebellum and cortex: radial migration
       • a. Granule neurons- Bergmann glia ---> guides outside to inside
         • b. Pyramidal neurons→ migrate along radial glia → guides inside to outside
           • c.Molecular regulation
             • Reelin protein: ECM It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones.
             • Doublecortin protein: DCX Doublecortin was found to bind to the microtubule cytoskeleton. In vivo and in vitro assays show that Doublecortin stabilizes microtubules and causes bundling. Knockout disorganization of CA3 of hippocampus
     • 2. Cortex: Tangential Migration.
       • Inhibitory GABAergic neurons
         • Migrate from lateral ganglionic eminence (LGE)
           • Dlx1, Dlx2 genes necessary migration
   • D. PNS
     • 1. Neural Crest
       • Migration route determines fate
     • 2 .Dorsal root ganglion cells
       • Adrenal gland, sympathetic and parasympathetic neurons, melanocytes, cartilage and bone