SUMMARY Growth of a properly complex dendrite arbor is a key step in neuronal differentiation and a prerequisite for neural circuit formation. Diverse cell surface molecules, such as the clustered protocadherins (Pcdhs), have long been proposed to regulate circuit formation through specific cell-cell interactions. Here, using transgenic and conditional knockout mice to manipulate γ-Pcdh repertoire in the cerebral cortex, we show that the complexity of a neuron’s dendritic arbor is determined by homophilic interactions with other cells. Neurons expressing only one of the 22 γ-Pcdhs can exhibit either exuberant, or minimal, dendrite complexity depending only on whether surrounding cells express the same isoform. Furthermore, loss of astrocytic γ-Pcdhs, or disruption of astrocyte-neuron homophilic matching, reduces dendrite complexity cell non-autonomously. Our data indicate that γ-Pcdhs act locally to promote dendrite arborization via homophilic matching and confirm that connectivity in vivo depends on molecular interactions between neurons, and between neurons and astrocytes.

SUMMARY The 22 γ-Protocadherin (γ-Pcdh) cell adhesion molecules are critical for the elaboration of complex dendritic arbors in the cerebral cortex. Here, we provide evidence that the γ-Pcdhs negatively regulate synapse development by inhibiting the postsynaptic cell adhesion molecule neuroligin-1 (Nlg1). Mice lacking all γ-Pcdhs in the forebrain exhibit significantly increased dendritic spine density in vivo, while spine density is significantly decreased in mice overexpressing one of the 22 γ-Pcdh isoforms. Co-expression of γ-Pcdhs inhibits the ability of Nlg1 to increase spine density and to induce presynaptic differentiation in hippocampal neurons in vitro. The γ-Pcdhs physically interact in cis with Nlg1 both in vitro and in vivo, and we present evidence that this disrupts Nlg1 binding to its presynaptic partner neurexin1β. Together with prior work, these data identify a mechanism through which γ-Pcdhs could coordinate dendrite arbor growth and complexity with spine maturation in the developing brain.

The proper formation of dendritic arbors is a critical step in neural circuit formation, and as such defects in arborization are associated with a variety of neurodevelopmental disorders. Among the best gene candidates are those encoding cell adhesion molecules, including members of the diverse cadherin superfamily characterized by distinctive, repeated adhesive domains in their extracellular regions. Protocadherins (Pcdhs) make up the largest group within this superfamily, encompassing over 80 genes, including the ∼60 genes of the α-, β-, and γ-Pcdh gene clusters and the non-clustered δ-Pcdh genes. An additional group includes the atypical cadherin genes encoding the giant Fat and Dachsous proteins and the 7-transmembrane cadherins. In this review we highlight the many roles that Pcdhs and atypical cadherins have been demonstrated to play in dendritogenesis, dendrite arborization, and dendritic spine regulation. Together, the published studies we discuss implicate these members of the cadherin superfamily as key regulators of dendrite development and function, and as potential therapeutic targets for future interventions in neurodevelopmental disorders.

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honors student and began my career in science. My first research project required me to sit in a dark room with a microscope and transfer 300 tiny Caenorhabditis elegans worms to an agar plate, a feat that, at that time, took me four hours to accomplish, but presently would take me less than 15 minutes. Little did I know I would end up working on my PhD just down the hall from my undergraduate honors research lab in the exact same dark room with yet another microscope on a project involving mouse neurons instead of worm gonads. This work would not have been possible without the guidance and mentorship of Josh. With his support I have performed and published novel research that I was able to present coast to coast for multiple years, something that would not have been possible without him. Any success I have moving forward will largely be owed to the examples and standards he set. I would also like to thank the current members of the Weiner Lab, Leah Fuller, Peter Bosch, Karmen Mah, Stacey Peek, David Steffen, and Charles Marcucci IV. I would especially like to thank Leah for helping me master the ways of the mouse, and Dr. Peter Bosch for both constructive and unconstructive conversations about experiments and general lab business. Thank you also to Dr. Austin Keeler for his guidance during our overlap in the Weiner lab. Thank you to Drs. Andrew Garrett, Dietmar Schreiner, and Jason Radley for their work and helpful comments. Also, thanks to a plethora of undergraduates, some of whom contributed to my projects, especially Dillan Newbold, Nora Koblesky, and Jake McDonough. I am grateful to the members of my thesis committee, Drs. Sarit Smolikove (who also got me started in research as an undergraduate), Michael Dailey, Ginny Willour, and Andy Frank, as well as Genetics Program Director Dr. Dan Eberl, for their encouragement and helpful suggestions during my graduate career. iii Thank you to Megan Astell for putting up with me while I "scienced" in the lab. Finally and most importantly, I would like to thank my parents John and Cathy for their continual support and for teaching me that education is the one thing that no one can take away from you. This extends to my brothers Matthew and Jacob for reasons words cannot describe.