PT  - JOURNAL ARTICLE
AU  - Gareth T. Powell
AU  - Yuguang Zhao
AU  - Ana Faro
AU  - Heather Stickney
AU  - Laura Novellasdemunt
AU  - Pedro Henriques
AU  - Gaia Gestri
AU  - Esther Redhouse White
AU  - Jingshan Ren
AU  - Weixian Lu
AU  - Rodrigo M. Young
AU  - Thomas A. Hawkins
AU  - Florencia Cavodeassi
AU  - Quenten Schwarz
AU  - Elena Dreosti
AU  - David W. Raible
AU  - Vivian S. W. Li
AU  - Gavin J. Wright
AU  - E. Yvonne Jones
AU  - Stephen W. Wilson
TI  - Cachd1 is a novel Frizzled- and LRP6-interacting protein required for neurons to acquire left-right asymmetric character
AID  - 10.1101/2022.05.16.492129
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.16.492129
4099  - http://biorxiv.org/content/early/2022/05/17/2022.05.16.492129.short
4100  - http://biorxiv.org/content/early/2022/05/17/2022.05.16.492129.full
AB  - Neurons on left and right sides of the nervous system frequently show asymmetric properties but how these differences arise is poorly understood. Through a forward genetic screen in zebrafish, we find that loss of function of the transmembrane protein Cachd1 results in right-sided habenular neurons adopting left-sided character. Cachd1 is expressed in habenular neuron progenitors, functions symmetrically downstream of asymmetric environmental signals that determine laterality and influences timing of the normally left-right asymmetric patterns of neurogenesis. Unbiased screening for Cachd1 partners identified the Wnt co-receptor Frizzled7 and further biochemical and structural analysis revealed Cachd1 can bind simultaneously to Fzd proteins and Lrp6, bridging between these two Wnt co-receptors. Consistent with these structural studies, lrp6 mutant zebrafish show symmetric habenulae with left-sided character and epistasis experiments with other Wnt pathway genes support an in vivo role for Cachd1 in modulating Wnt pathway activity in the brain. Together, these studies identify Cachd1 as a novel Wnt-receptor interacting protein with roles in regulating neurogenesis and neuronal identity.Competing Interest StatementThe authors have declared no competing interest.