Motor pools organization depends on the combined function of N-cadherin and type II cadherins

Abstract

Type I and type II classical cadherins constitute a family of cell adhesion molecules expressed in complex combinatorial profiles in the nervous system, suggesting that a cadherin code implements specific adhesive recognition events that control the development of neural circuits. In the spinal cord, classical cadherins define at a molecular level the positional organization of motor neuron subtypes into discrete nuclear structures termed motor pools. However, the roles and contributions of different members of the family in defining motor neuron spatial organization are not yet clear. By combining mouse genetics with quantitative positional analysis, we found that motor neuron organization into pools depends on type II cadherins. Type II cadherin function, however, does not strictly reflect the predictions arising from binding specificities at a molecular level, but instead relies on N-cadherin, a type I cadherin whose elimination is required to reveal type II contributions.

Redundant type II cadherins define neuroepithelial cell states for cytoarchitectonic robustness

“…We next generated mice deficient for each Cdh locus by intercrossing to show that these mice are virtually viable and fertile with no fatal phenotype, which is in line with previous series of reports 31,[36][37][38][39] . Using western blotting in tissues derived from these single KO mice, we also confirmed that manipulated alleles for the three type II Cdh genes are all protein null (Fig.…”

“…Gain of function studies for Cdh subclasses in vivo have accordingly revealed that differential and dynamic Cdh expression switches are crucial in neurulation 29 , 30 , compartmentalization 31 , neural crest emigration 32 , and precise positioning of spinal motor neurons 33 during early development. However, loss of function studies using mouse indicated that, in striking contrast with the early embryonic lethal phenotype for type I Cdh1 (=E-cadherin)-/- 34 or Cdh2 (=N-cadherin)-/- 35 mice, most type II Cdh single knockout mice and some combinatorial mutants show few embryonic phenotypes despite the considerable levels of early expression 31 , 36 – 39 . This has often been ascribed to “molecular and/or functional redundancy” of Cdhs, yet no direct evidence for their necessity in early embryogenesis is provided thus far.…”

Cadherins regulate nuclear topography and function of developing ocular motor circuitry

“…We find that several cadherins, including cdh2 and cdh11 , are expressed by all subnuclei, highlighting them as prime candidates to drive baseline levels of adhesion via homophilic interactions. Recent work raises the possibility that heterophilic interactions between type II cadherins belonging to specificity groups, such as cdh8 (expressed to varying degrees by IR/MR and SR) and cdh11 (expressed by all ocular motor neurons), could also participate, in collaboration with cdh2 ( Brasch et al, 2018 ; Dewitz et al, 2019 ).…”

“…To date, the molecular and cellular processes which give rise to subnuclear topography remain unknown. The positioning of some groups of motor neurons has been shown to be regulated by members of the classical cadherin superfamily of cell adhesion molecules, which include type I and type II cadherins ( Price et al, 2002 ; Demireva et al, 2011 ; Astick et al, 2014 ; Dewitz et al, 2018 ; Dewitz et al, 2019 ). Differential expression of type II cadherins, which participate in homophilic as well as heterophilic interactions ( Patel et al, 2006 ), drives the segregation and coalescence of somatomotor and branchiomotor neurons into discrete cranial motor nuclei in the hindbrain ( Astick et al, 2014 ).…”

Brain wiring with composite instructions

“…This gave rise to the hypothesis of functional redundancy and the systematic analysis of double and triple knock-outs for closely related family members. [59,60,62] For example, a triple knock-out of Cadherins 6, 9, and 10 causes a highly specific defect in the wiring of the retina, [60] but no defect in the sorting of motor pools in the spinal cord. [62] The triple-knock-out mice are viable and fertile.…”