The role of cell surface diversity in neural circuit assembly
During brain development, the assembly of functional neural circuits requires mechanisms to connect different neurons. Crucial to this process is the ability of neurites (axons and dendrites) of individual neurons to distinguish between themselves and neurites from other neurons. This mechanism is known as self-avoidance and requires that, in principle, every neuron must express a unique combination of cell-surface recognition molecules to generate a molecular recognition code, i.e. an identity.
The long-term goal of our laboratory is to dissect the molecular mechanisms behind the generation of such code in mammals.
Clustered Protocadherins genes: a code for neural cell-surface diversity
In mammals, the generation of cell-surface diversity requires stochastic and combinatorial expression of a small subset of clustered Protocadherin (Pcdh) genes, randomly chosen from a total of 60. This is a remarkable task especially given that these 60 nearly-identical genes are organized in tandem and are sequestered within a chromatin state, doubly locked by DNA and H3K9 methylation and thus generally refractive to transcription.
At the core of such elegant mechanism for the generation of protein isoform diversity, two fundamental questions remained unanswered: How is random choice of a small number of nearly identical genes achieved? How does localized expression occur in a repressive environment? We use genomic, genetics, biochemical and biophysical approaches to dissect the exquisite coupling between the 3D chromosome architecture, the underlying chromatin structure, transcription and RNA processing that enables the generation of such enormous diversity of molecular identities in neurons.
“The Pcdh gene cluster: an architectural masterpiece” T. Maniatis
WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring
Kiefer L.*, Chiosso A.*, Langen J.*, Buckley A.*, Gaudin S., Rajkumar S.M.†, Servito G.I.F.†, Cha E.S., Vijay A., Yeung A., Horta A., Mui M.H., Canzio D.
Cohesin erases genomic-proximity biases to drive stochastic Protocadherin expression for proper neural wiring
Kiefer L.*, Servito G.I.F.*, Rajkumar S.M.*, Langen J.*, Chiosso A.*, Buckley A., Cha E.S., Horta A., Mui M.H., Canzio D.
Antisense lncRNA transcription mediates DNA demethylation to drive stochastic Protocadherin α promoter choice
Canzio D., Nwakeze C., Horta A., Rajkumar S., Coffey E., Duffy E., Duffie’ R., Monahan K., O’Keeffe S., Simon M., Lomvardas S., Maniatis T.
Clustered Protocadherin methylation alterations in cancer
Clinical Epigenetics (2019)
Vega-Benedetti A.F., Loi E., Moi L., Blois S., Fadda A., Antonelli M., Arcella A., Badiali M., Giangaspero F., Morra I., Columbano A., Restivo A., Zorcolo L., Gismondi V., Varesco L., Bellomo S.K., Giordano S., Canale M., Casadei-Gardini A., Faloppi L., Puzzoni M., Scartozzi M., Ziranu P., Cabras G., Cocco P., Ennas M. G., Satta G., Zucca M., Canzio D., Zavattari P.
Writing, reading, and translating the clustered Protocadherin cell surface recognition code for neural circuit assembly
Mountoufaris G., Canzio D., Nwakeze CL., Chen WV., Maniatis T.
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Daniele was born in Rieti, Italy. He received his Bachelor of Science in Biochemistry from the University of California, Santa Barbara and his PhD in Chemical Biology from the University of California, San Francisco under the guidance of Dr. Geeta Narlikar. He then moved to New York City for his postdoctoral training in the laboratory of Tom Maniatis at Columbia University. When not in lab, Daniele loves riding his bike and spending time with Mocha.
Lea Kiefer was born and raised near Mannheim, Germany. She moved to the United States to pursue a Bacherlor’s degree in Biochemistry with a minor in Mathematics. She then relocated to the East Coast for graduate school and received her PhD in Molecular Biophysics and Biochemistry from Yale University in 2020 under the guidance of Dr. Matt Simon. Besides her postdoctoral training in the Canzio lab, Lea enjoys the outdoors through hiking and camping.
UCSF, Neuroscience Graduate Student
Jenn was born and raised in Pasadena, a suburb of Los Angeles, CA. She attended the University of Southern California for her undergraduate studies, where she received her B.A. in Neuroscience. Before relocating to the Bay Area as a Neuroscience PhD student, she worked as an undergraduate researcher and lab technician with Dr. Karen Chang at USC. When not thinking about clustered Protocadherins, Jenn keeps herself busy with random artistic pursuits and baking.
UCSF, Neuroscience Graduate Student
Alex grew up in the San Francisco Bay Area and went to undergrad at Washington University in St. Louis. He then teched for two years in the lab of Evan Macosko at the Broad Institute before joining the neuroscience program at UCSF. His interest in how neurons acquire their intricate morphologies and wiring patterns drew him to the study of protocadherins. He loves playing tennis, exploring new places, and going on coffee runs with his lab mates.
Michael was born in Hong Kong and was raised in San Francisco, CA. He received his B.S. in Animal Science from UC Davis. Prior to joining the Canzio lab, he was an animal technician at UCSF. Michael is joined between the Canzio and the Paredes labs at UCSF. When not in lab, Michael likes to watch movies, draw, and spend time with his dog.
Born in La Rochelle and raised on a small island off the west coast of France, Simon graduated from the Ecole Normale Supérieure de Lyon with a bachelor’s degree in Biology and from Sorbonne University with a master’s degree in Molecular Biology. Interested in all things loop extrusion, he interned in the Giorgetti lab (FMI Basel) and Goloborodko lab (IMBA Vienna) before joining the Canzio lab. Besides chromosome biology, Simon enjoys being outdoors, running, and reading.
Mocha is a New Yorker. Prior to joining the Canzio lab she “worked” as a happy doggie in Daniele’s house.
(PhD student in Biochemistry, Cell & Molecular Biology, Weill Cornell)
(PhD student in Chemical Biology, Biochemistry, & Biophysics, UC Santa Cruz)
(MD/PhD student, UCLA)
(PhD Student in Neuroscience, University of Zurich)
(Research Technician, Weill Cornell)
(Research Technician, University of Pennsylvania)
UCSF Weill Institute for Neurosciences
1651 4th Street, 4th floor
San Francisco, CA, 94158, USA