It is believed that understanding of molecular profile in the rhomboideus motor pool is critical to explore the spinal motor neuronal organization (Nicholas Stafini, 2014). Despite knowing different expression profile of transcription factors determines each class of motor neurons and facilitates motor pool segregation (Shirasaki and Pfaff, 2002; Pattyn et al., 2003). It is still astonishing to find that nature utilizes a combination of differential expression of a protein family to identify cell types during the development. In the study of Astick et al., 2014, they found individuals of eight distinct motor nuclei in rhombomere 5 (r5) and rhombomere 8 (r8) are identified by a combinational expression of six type II cadherins (shown in Figure2). They reported that somatomotor and branchiomotor nuclei would first undergo a period where they mingle together prior to their segregation regardless of their birthplace.

How could single cell distinguish from each other only by having different proteins expressed? And how do they recognize each other in such an intermingled phase? There must be some protein-protein interactions happening inside. Indeed, cadherins are reported to interact with adjacent cells in a homophilic fashion to achieve heterogeneous cell sorting (Price et al., 2002; Shirabe et al., 2005; Patel et al., 2005).

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To investigate the requirement of cadherins during cranial motor neuron coalescence, Astick and colleagues conditionally expressed a negative form of cadherin N?390 in cranial motor neuron progenitors by electroporation to disrupt cadherin-mediated functions. It turned out that cranial motor neurons without cadherin activity failed to aggregate to cluster pools in r5 and r8, while cellular differentiation and migration remain unchanged. Following the identification of cadherin code, they further test whether the ablation or insertion of the unique cadherin in other type motor neurons would affect their coalescence. As expected, abnormal cadherin expressions led to coalescence failure but had no effect on neuron generation and differentiation (Astick et al.

, 2014).Most interestingly, these cadherin codes are compiled before nucleogenesis (Pearson et al., 2014).

This begs the question of how and when exactly is this code established? Does it happen in the phase where the molecular identity of spinal motor neurons matures? If this step is under the control of certain transcription factors, then this combination code would provide a clear direction for future research of gene expression dynamics. Moreover, beyond this cadherin code, will there be a more general principle that controls cadherin function in motor neuron organization? Undeniably, apart from defining motor pool identities, type II cadherins expressions can also be found in sensory neurons, which implicates potential roles of cadherin in establishing the sensory-motor circuits during development (Price et al., 2002). This discovery also provides clinical implications for motor neuron regeneration therapies since that requires particular motor neurons with desired identities to join the original neuronal circuit at proper positions and to project to their target organs (Stafini, 2014). However, mechanisms like the biochemical interactions of proteins behind this code remain elusive. Given that the EC1 domain of cadherins plays a key role in cadherin functional activity (Patel et al.

, 2005, what kind of interactions could these different motor neurons perform to achieve this identity-based clustering? A recent study by Montague et al., 2017 observed spontaneous calcium activity being a concomitant to nucleogenesis process, raising the possibility that neural circuitry is also governed by spontaneous activity and cadherin networks interplay.