The organization of behavior: A neuropsychological theory

Evolution and diversity of cadherins and catenins.

THE goal of chemistry is the determination of the atomic arrangement in space, which will be able to account for all the properties of matter under consideration. The greatest achievements in this direction have been obtained by the application of purely chemical methods, essentially because of the wonderful artistic skill of generations of chemists. Since von Laue's discovery of the diffraction of X-rays, and Sir William and W. L. Bragg's first X-ray analysis of the crystalline state, however, the way has been opened to a much more intimate knowledge of the atomic pattern. It is characteristic that the first results of the X-ray method dealt with the stereochemistry of the solid state, which always had been nearly impossible to attack with previous methods. The X-ray method afterwards proved to be no less important for the structural analysis of liquids and of single molecules in the gaseous state, and this side of the development is by no means neglected in the first volume of the work before us; the title seems adequate because of the preponderant role the crystalline state has played in the great majority of investigations. The Crystalline State. Edited by Sir William Bragg Dr. W. L. Bragg. Vol. 1: A General Survey. By W. L. Bragg. Pp. xiv + 352 + 32 plates. (London: G. Bell and Sons, Ltd., 1933.) 26s. net.

The Crystalline State

Adhesion Protein Structure, Molecular Affinities, and Principles of Cell-Cell Recognition

Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy

As the brain develops, its basic building blocks – cells called neurons – need to form the correct connections with one another in order to give rise to neural circuits A mistake that leads to the formation of incorrect connections can result in a number of disorders or brain abnormalities Proteins called cadherins that are present on the surface of neurons enable them to stick to their correct partners like Velcro One of these proteins is called Protocadherin-19 However, it was not fully understood how this protein forms an adhesive bond with other Protocadherin-19 molecules, or how some of the proteins within the cadherin family are able to distinguish between one another Cooper et al used X-ray crystallography to visualize the molecular structure of Protocadherin-19 taken from zebrafish in order to better understand the adhesive bond that these proteins form with each other In addition, the new structure showed the sites of the mutations that cause a form of epilepsy in infant females From this, Cooper et al could predict how the mutations would disrupt Protocadherin-19’s shape and function The structures revealed that Protocadherin-19 molecules from adjacent cells engage in a “forearm handshake” to form the bond that connects neurons Some of the mutations that cause epilepsy occur in the region responsible for this Protocadherin-19 forearm handshake Laboratory experiments confirmed that these mutations impair the formation of the adhesive bond, revealing the molecular basis for some of the mutations that underlie Protocadherin-19-female-limited epilepsy Other cadherin molecules may interact via a similar forearm handshake; this could be investigated in future experiments It also remains to be discovered how brain wiring depends on Protocadherin-19 adhesion in animal development, and how altering these proteins can rewire developing brain circuits

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Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy

Cell–cell recognition guides the assembly of the vertebrate brain during development. δ-Protocadherins comprise a family of neural adhesion molecules that are differentially expressed and have been implicated in a range of neurodevelopmental disorders. Here we show that the expression of δ-protocadherins partitions the zebrafish optic tectum into radial columns of neurons. Using in vivo two-photon imaging of bacterial artificial chromosome transgenic zebrafish, we show that pcdh19 is expressed in discrete columns of neurons, and that these columnar modules are derived from proliferative pcdh19+ neuroepithelial precursors. Elimination of pcdh19 results in both a disruption of columnar organization and defects in visually guided behaviors. These results reveal a fundamental mechanism for organizing the developing nervous system: subdivision of the early neuroepithelium into precursors with distinct molecular identities guides the autonomous development of parallel neuronal units, organizing neural circuit formation and behavior.

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Protocadherins Control the Modular Assembly of Neuronal Columns in the Zebrafish Optic Tectum

...............................................................................................................................ii Acknowledgments................................................................................................................ v Vita ...................................................................................................................................... vi List of Tables ........................................................................................................................ x List of Figures ...................................................................................................................... xi Chapter 1: Introduction ...................................................................................................... 1 The Cadherin Superfamily and Adhesion .............................................................. 3 Neural Circuitry, Neurodevelopmental Disease, and the δ-Protocadherins ...... 19 Pcdh19 Female Epilepsy ...................................................................................... 25 Zebrafish as a Neurodevelopmental Model ........................................................ 30 Multidisciplinary Approach to a Fundamental Question .................................... 34 Chapter 2: Protocadherins Control the Modular Assembly of Neuronal Columns in the Zebrafish Optic Tectum ..................................................................................................... 40 Abstract ............................................................................................................... 40 Introduction ......................................................................................................... 41 Results and Discussion ........................................................................................ 42 Materials and Methods ....................................................................................... 48

Sharon R Cooper

Papers

Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy

Protocadherins Control the Modular Assembly of Neuronal Columns in the Zebrafish Optic Tectum

δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry

Author response: Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy