How does a single cell make a brain??? Neural Development How does a single cell make a brain??? How are different brain regions specified??? 1

How do cells become neurons? Environmental factors Positional cues Neural Development How do cells become neurons? Environmental factors Positional cues Genetic factors Competence Cell lineage Timing 2

Neural Development depends on genes and environment Keywords in Development Induction: Cells are instructed to adopt a fate by signals in the environment. Competence: the ability of a cell to respond to a signal. It depends on the receptors, transcription factors, etc expressed by the cell. Differentiation: Cell elaborates a specific developmental program. Determination: A cell is restricted in its developmental potential. 3

Major Processes in Development egg embryo 1n + 1n = 2n 1. Mitosis -cell division 2. Patterning -cells are arranged in proper positions -the body plan is established 3. Differentiation -cells become different from each other -they acquire specific functions 4

Initial Steps in the Development of the Nervous System: Fertilization Cleavage Gastrulation Neurulation 5

Looking at early development of the nervous system: Xenopus Frog Cleavage Gastrulation Fertilization Neurulation 6

Early events in neural development Gastrulation : Gastrulation is the process by which the embryo acquires 3 germ layers. There is intense cell movement and rearrangement Ectoderm Major tissues of the Nervous System, Epidermis Mesoderm Connective Tissue, Muscle, Vessels Endoderm  guts, lungs, liver 7

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Early events in neural development Gastrulation Neurulation 9

Neurulation: Formation of the Neural Tube After Gastrulation comes Neurulation. During Neurulation, the neural plate invaginates, and the neural folds close to form the neural tube. 10

PNS (sensory ganglia, ANS), melanocytes, adrenal medula Long After Neurulation: Neural Tube Neural Crest Rostral Caudal PNS (sensory ganglia, ANS), melanocytes, adrenal medula Brain Spinal Cord 11

- How do cells become neurons? 12

Early events in neural development Gastrulation Neurulation 13

Classic experiment showing the induction of the nervous system Hans Spemann discovered the organizer----Nobel 1935 Expt: Transplant different parts of the developing embryo (donor) into another embryo (host) Result: 1) If the dorsal lip is transplanted, a second embryonic axis forms 2) The second embryo has both host and donor tissue Take the DLB from a pigmented donor and place it on the ventral ectoderm (epidermal future) of a host. The differentiation of the NEURAL PLATE from the uncommitted ectoderm in amphibian embryos depends on signals secreted by a specialized group of cells called the organizer regions. 14

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Model: Inductive signal in dorsal lip instructs ectoderm The organizer region is responsible for converting ectoderm into neural cells Model: Inductive signal in dorsal lip instructs ectoderm 16

How does the organizer instruct epidermal cells? Experiment: Dissociate animal cap, grow in culture Result: Neurons can form in the absence of the organizer The default is to become neural Model: Epidermis makes local signal that inhibits neural fate 17

How does the organizer instruct epidermal cells? Experiment: Inject blastula with genes of interest. Do any cause animal cap to become neural? Result: Expression of a dominant negative mutant of a BMP receptor results in neural fate. Model: BMP signal instructs cells not to become neural 18

Activation of BMP signaling inhibits the neural fate NOT NEURAL BMP signaling: receptor serine kinase 19

How does the organizer instruct epidermal cells? Experiment: Inject blastocyst with genes from the organizer and see if any cause the animal cap to become neural Neural fate (?) Take the animal cap Inject mRNAs Noggin is a secreted protein, expressed in the organizer and later in the notocord. Noggin inhibits BMP signaling. Follistatin and chordin have similar functions. 20

Inhibition of BMP signaling makes cells adopt neural fate == NOGGIN NEURAL 21

Current Model for how cells become neural Default state is neural Local secretion of BMPs by epidermis inhibits neural fate Local secretion of noggin, chordin by dorsal lip or mesoderm inhibits BMP signaling Inhibition of BMP signaling give rise to neural fate Double Inhibition Model for Neural fate 22

Model: The ‘double inhibition model’ for neural fate 23

A cell’s fate will depend on the signals to which it is exposed as well as the developmental history of the cell (which genes they express) 24