The tandem–random transition of cellular patterning: proposed roles of N‐cadherin‐based orientational cell adhesions in the development, maintenance, and degeneration of the nucleus pulposus

Intervertebral disc degeneration (IDD) can contribute to lower back and neck pain. In IDD, the most affected component of the intervertebral disc is the nucleus pulposus (NP). Derived from the notochord, where cells are organized into a tandem configuration, young NP cells cluster in three-dimensional (3D) networks embedded in a gelatinous matrix. Here, we review the current understanding of NP development, homeostasis, physiology, and degeneration with a focus on the roles of the cell adhesion molecule N-cadherin in these processes. Based on the literature, we hypothesize that N-cadherin contributes to the architectural transition from the notochord to the NP by mediating a switch in cellular organization from tandem to random orientational cell adhesions (OCAs). We further hypothesize that the 3D clustering of NP cells may facilitate N-cadherin to act as a mechanosensor to modulate NP gene expression under mechanical stresses. We hope these hypotheses promote future research on the etiology of human IDD and the development of measures to prevent and treat IDD. Some open questions on N-cadherin functions in the NP are also discussed.