Molecular Mechanisms of Neural Induction. 1. During development ...

Bio 3411, Fall 2005Aguan Wei979 McDonnell Sciences Building, Medical School Campus, WUMS.email: weia@thalamus.wustl.eduLecture 18 – Molecular Mechanisms of Neural Induction.1. During development, embryonic cells signal to each other with secreted diffusiblemolecules that instruct neighboring cells to change their pattern of gene expression.This signaling event is termed induction. Because the signaling molecule instructsthe developmental fate of the recipient cell, it is called a morphogen.2. Induction is observed in classic experiments manipulating amphibian blastula:a. (1924) Hilde Mangold and Hans Spemann. Transplanting the dorsal lip ofthe blastopore (presumptive mesoderm) from one embryo (in late blastulastage) to the ventral pole of a second embryo (same late blastula stage) resultsin an embryo with a second neuroaxis! The transplanted tissue is capable of“organizing” a second neuroaxis, so this region of the embryo is termed the“Mangold-Spemann Organizer”.b. (1969) Pieter Nieuwkoop, (1989) Grunz and Tacke, (1991) Godsave andSlack. Isolated animal caps (neuroectodermal cells) from blastulas can becultured in vitro. Unlike the embryo, cultured intact animal caps develop intoepidermal cells, instead of neurons. However, dissociated animal cap cellsdevelop into neurons. Close contact between developing neuroectodermalcells results in expression of epidermal cell fate, whereas loss of close contactresults in neuronal cell fate.c. These two classic experiments form the basis for the molecular analysis ofneural induction.3. Experimental manipulations show that inductive signaling occurs betweenneighboring cells of the developing neuroectoderm, and between developingneuroectoderm and mesoderm to generate the neural plate. Normal morphogenicmovements during gastrulation permit induction to occur, by placing signalingand recipient tissues together in close apposition.4. Developing neuroectodermal cells secrete a protein which signals neighboring cells toinhibit the neural fate and promote the epidermal fate. This signaling protein is BoneMorphogenic Protein-4 (BMP-4), a member of the Transforming Growth Factorβ(TGF-β) family of proteins.Experimental evidence; (1990-1994) Ali Hemmati-Brivanlou and Doug Melton:a) Expression of exogenous dominant-negative TGF-β receptors, blocks thefunction of native TGF-β receptors, leading to neuronal differentiation byintact animal caps.b) BMP-4 is expressed in neuroectodermal cells.c) Addition of BMP-4 to cultures of dissociated animal caps, causesdifferentiation of epidermal cells, due to repression of the neural fate.1

Neurogenesis: Inductive Mechanisms in a Nutshell.1. Neuroectodermal cells choose either a neuronal or epidermalcell fate.2. Interactions between mesoderm and neuroectoderm induceneuroectoderm to adopt the neural fate.3. Induction acts through signaling by a secreted protein, BoneMorphogenic Protein-4 (BMP-4), made by neuroectodermalcells.4. BMP-4 inhibits neuralization and promotes the epidermal fatein neighboring cells.5. Mesodermal cells secrete proteins (Chordin, Noggin,Follistatin) which directly bind and antagonize BMP-4 activity.6. Neuroectodermal cells become neurons by suppression ofBMP-4 activity by secreted proteins from underlyingmesodermal cells.7. The “default” state of neuroectodermal cells is neuronal.8. This inductive mechanism is conserved between vertebratesand invertebrates.9. BMP-4 is a member of the Transforming Growth Factor (TGF-β)family of signaling molecules. Similar signaling events maybelocally re-employed later in the developing nervous system.4