Cadherins in Cerebellar Development: Translation of Embryonic Patterning into Mature Functional Compartmentalization

Abstract

Cadherins are cell adhesion molecules with multiple morphogenic functions in brain development, for example, in neuroblast migration and aggregation, axon navigation, neural circuit formation, and synaptogenesis. More than 100 members of the cadherin superfamily are expressed in the developing and mature brain. Most of the cadherins investigated, in particular classic cadherins and δ-protocadherins, are expressed in the cerebellum. For several cadherin subtypes, expression begins at early embryonic stages and persists until mature stages of cerebellar development. At intermediate stages, distinct Purkinje cell clusters exhibit unique rostrocaudal and mediolateral expression profiles for each cadherin. In the chicken, mouse, and other species, the Purkinje cell clusters are separated by intervening raphes of migrating granule cells. This pattern of Purkinje cell clusters/raphes is, at least in part, continuous with the parasagittal striping pattern that is apparent in the mature cerebellar cortex, for example, for zebrin II/aldolase C. Moreover, subregions of the deep cerebellar nuclei, vestibular nuclei and the olivary complex also express cadherins differentially. Neuroanatomical evidence suggests that the nuclear subregions and cortical domains that express the same cadherin subtype are connected to each other, to form neural subcircuits of the cerebellar system. Cadherins thus provide a molecular code that specifies not only embryonic structures but also functional cerebellar compartmentalization. By following the implementation of this code, it can be revealed how mature functional architecture emerges from embryonic patterning during cerebellar development. Dysfunction of some cadherins is associated with psychiatric diseases and developmental impairments and may also affect cerebellar function.

Contribution of Genoarchitecture to Understanding Hippocampal Evolution and Development

“…The embryonic origin of neurons determines much of their phenotype, including connections [Gilbert, 2000]; axons navigate through permissive developmentally defined molecular domains [Shimamura et al, 1995] that are recognized by way of ligand-receptor mechanisms [Tessier-Lavigne and Goodman, 1996;Kolodkin and Tessier-Lavigne, 2011] and establish contacts with cells on the basis of their expression of membrane molecules that are also determined by their site and date of origin [Redies et al, 2011]. Thus, developmental studies can offer relevant information for understanding the organizing principles of the brain connectome and predict both fiber tract trajectories and targets .…”

“…For example, in the spinal cord, the LIM-hd TF Islet1 regulate the expression of Neuropilin 1 and Slit2 [Lee et al, 2015], molecules related to the Robo-Slit and Neuropilin-Semaphorin ligand-receptor signaling that play a role in guidance during cell migration and axonal pathfinding [Tessier-Lavigne and Goodman, 1996]. In the thalamus, Lhx2 and Lhx9 were shown to regulate the expression of Protocadherin 10 [Peukert et al, 2011], a molecule of the cadherin/protocadherin family that has been involved in cell aggregation, axonal pathfinding, and synaptogenesis by homotypic binding of structures expressing the same combinatorial molecular code [Redies, 2000;Neudert and Redies, 2008;Redies et al, 2011].…”

“…This explains the formation of parallel circuits between matched neuron subpopulations of DG, CA3, and CA1 [Deguchi et al, 2011;commented by Moser, 2011] and opens the avenue for additional studies on the connections of the HF, including those with other structures sharing expression of similar combinations of molecules. For example, this can initially match forebrain structures expressing Lhx9 (including HF and parts of the amygdala, septum, and hypothalamus that also express Lhx9), but we know that neurons born at different time windows express different combinations of cadherins/ protocadherins [Redies et al, 2011], thus refining the prediction to match sets of neurons of the Lhx9-expressing domains (and expressing additional factors) that may end having the same molecular code of cadherins/protocadherins and other molecules involved in circuit formation. The connections may also be first established with transient cells showing the same molecular profile, such as those of the subplate for the thalamocortical projections [Kanold and Luhmann, 2010] or Cajal-Retzius cells for the projection from the EC to DG [Förster et al, 2006].…”

Cerebellar Zones: History, Development, and Function

“…In this special issue, Redies provides a review of this extensive literature with detailed characterization of cadherinexpressing Purkinje cell stripes and their transient separation by granule cell raphes [36]. The issues that are very nicely discussed include the relationship between embryonic and adult stripes and zones, and the homotypic binding model whereby the precision of cerebellar cell migration as well as afferent and efferent zonal connections are thought to be guided by mutual expression of the same cadherin gene.…”

Adhesive/Repulsive Codes in Vertebrate Forebrain Morphogenesis

“…Regionalized expression of different types of cadherins has also been shown to promote cell segregation. Indeed, cadherins show regionally restricted patterns of expression in a variety of developmental contexts, and their tissue-specific expression often coincides with the presence of sharp boundaries between domains of expression (i.e., [30][31][32][33][34][35][36]). In the mouse telencephalon for example, the complementary expression of cadherin-6 and R-cadherin promotes segregation between cortex and striatum [34].…”