Seven-pass transmembrane cadherins: roles and emerging mechanisms in axonal and dendritic patterning

Abstract

The Flamingo/Celsr seven-transmembrane cadherins represent a conserved subgroup of the cadherin superfamily involved in multiple aspects of development. In the developing nervous system, Fmi/Celsr control axonal blueprint and dendritic morphogenesis from invertebrates to mammals. As expected from their molecular structure, seven-transmembrane cadherins can induce cell-cell homophilic interactions but also intracellular signaling. Fmi/Celsr is known to regulate planar cell polarity (PCP) through interactions with PCP proteins. In the nervous system, Fmi/Celsr can function in collaboration with or independently of other PCP genes. Here, we focus on recent studies which show that seven-transmembrane cadherins use distinct molecular mechanisms to achieve diverse functions in the development of the nervous system.

Fig. 1

Molecular structure of Fmi/Celsr family members. Flamingo and Celsr extracellular domains comprises nine cadherin repeats, a series of EGF-like and laminin globular-like domains, and a hormone receptor domain (HRM). The seven-transmembrane domain, similar to those found in GPCRs, is characteristic of this atypical cadherin subfamily. The GPCR proteolytic site (GPS) is conserved in many adhesion GPCRs. The intracellular domain is generally not conserved and does not contain recognizable domains. Adapted from [2]

Fig. 2

Examples of Fmi/Celsr phenotypes in axon guidance and targeting. a In the Drosophila visual system, R8 photoreceptor axons are arranged in evenly spaced topographic arrays and target the M3 layer in the medulla. In fmi mutants, competitive axon–axon interactions are lost leading to an axon bundling phenotype. Moreover, R8 axons stop prematurely at the M1 layer due to impaired Fmi homophilic axon–target interactions. b Photoreceptor axons arrive in the fly lamina as an ommatidial bundle. Axons defasciculate and grow perpendicularly to the bundle in stereotyped directions to reach their correct target. In fmi mutants, axons make directional errors and innervate inappropriate targets. Adapted from [2]. c In mice, several axon tracts of the internal capsule are misguided in Celsr3 mutants, including subcerebral projections (CST, blue). These tracts are defective when Celsr3 is absent in these axons or in guidepost cell (red area), suggesting that Celsr3 regulates axon guidance via homophilic interactions. Adapted from [31]

Fig. 3

Roles of Fmi/Celsr in dendritic morphogenesis. a In Drosophila melanogaster larvae, dendrites of peripheral neurons cover their entire sensory field but always avoid dendrites of homologous neurons in the contralateral side. In fmi mutants, however, dendrodendritic competitive interactions are lost, and dendrites invade the contralateral hemisegment. b In rat neuronal cultures, knocking down Celsr2 or Celsr3 suppresses or enhances neurite growth, respectively

Fig. 4

Models of the diverse molecular mechanisms of seven-transmembrane cadherins in neuronal interactions and connections. a Fmi/Celsr could act as pure adhesive molecules, without transmitting an intracellular signal. b Fmi/Celsr may be a receptor for an unknown ligand. c In mammals, Celsr2 and Celsr3 homotypic interactions trigger intracellular calcium increase, leading to opposite responses in dendritogenesis. d Fzd3 collaborates with Celsr3 in the formation of axonal tracts in mammals. The other PCP proteins Vangl2, Dvl, and Wnts are also involved in the guidance of commissural axons in the mice spinal cord. e In the fly visual system, synaptic-layer targeting in the medulla is mediated by asymmetric homophilic interaction, involving Fmi and Gogo in photoreceptors and Fmi in their target. Gogo interacts with the cytoskeleton via Adducin