Dr. Weiner is currently not taking on new research students due to his administrative roles.

Research summary

Molecular mechanisms of neuronal differentiation and neural circuit formation

The mammalian brain is the most complex system in all of biology. The human brain has ~100 billion neurons and perhaps 500 trillion synapses, contact sites between neurons through which information flows. The differentiation of a vast array of distinct neuronal cell types from stem cell progenitors, their migration to form layers and clusters, and their differential survival are all key developmental steps that can be disrupted in human disorders such as microcephaly and lissencephaly. The elaboration of dendrites and axons and their formation of specific neural circuits underlies all mature function, and dysregulation of these processes underlies a wide variety of genetic and syndromic disorders, including forms of autism spectrum disorders, Down and Fragile X Syndromes, and schizophrenia. Over the past 35 years, my research has focused on identifying the fundamental molecular mechanisms that control neuronal differentiation and neural circuit formation during brain development. We have taken a gene candidate approach, generating allelic series of transgenic and knockout mice and analyzing their developmental phenotypes with a wide range of genetic, biochemical, pharmacological, molecular biology, and cell biology techniques. We focus on genes and processes that have been implicated in human neurodevelopmental disorders, primarily the clustered Protocadherin family of neuronal cell adhesion molecules.

Protocadherins

Three large clusters of cadherin-related genes (Protocadherin-α, -β, and -γ) lie in a tandem array on a single chromosome in mammals. The γ cluster, on which we have focused, consists of 22 "variable" exons, each of which encodes the extracellular, transmembrane, and partial cytoplasmic domains of a single protocadherin (Pcdh) isoform. Each variable exon is spliced to a set of three "constant" exons which encode a shared C-terminal domain. Thus, a variety of adhesive specificities can link into a common signaling pathway. Because each neuron expresses a small number of isoforms in a semi-stochastic manner, the γ-Pcdhs may provide a “molecular code” that helps specify cell-cell interactions. We have shown that the γ-Pcdhs act as homophilic adhesion molecules and have identified them as critical mediators of neuronal survival, proper dendrite arborization, and synaptogenesis in the cerebral cortex. Homophilic trans-interactions between specific γ-Pcdh isoforms on neurons and astrocytes regulates the extent of dendrite outgrowth in vivo. Additionally, cis-interactions between the γ-Pcdhs and the autism-associated protein neuroligin-1 regulate the formation of dendritic spines and excitatory synapses in the cortex. Importantly, epigenetic regulation of γ-Pcdh repertoire is disrupted in neurodevelopmental disorders, indicating that the mechanisms we’ve discovered have implications for both normal and disrupted human development. 

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