Effective axon regeneration is critical for restoring nerve function in patients with axon injury-related neurological diseases, yet adult mammals show limited regenerative capacity in central axonal branches of dorsal root ganglion (DRG) neurons compared to their peripheral counterparts. To explore molecular drivers of this difference, rat sciatic nerve or dorsal root axotomy was performed to examine the expression of dysbindin domain containing 2 (DBNDD2) in DRGs after regenerative peripheral or non-regenerative central axon injury. Results revealed DBNDD2 is down-regulated in DRGs post-peripheral injury but up-regulated after central injury. Additionally, DBNDD2 expression varies between neonatal and adult rat DRGs, increasing gradually with development. Functional tests via DBNDD2 knockdown demonstrated that silencing this gene promotes neurite outgrowth in both neonatal and adult DRG neurons and stimulates robust axon regeneration in adult rats following sciatic nerve crush injury. Bioinformatic analysis further identified that transcription factor estrogen receptor 1 (ESR1) interacts with DBNDD2, exhibits a similar expression trend post-axon injury, and may target DBNDD2. These findings suggest that reduced DBNDD2 levels after peripheral injury and low neonatal DBNDD2 abundance contribute to axon regeneration, highlighting DBNDD2 manipulation as a promising therapeutic strategy for improving recovery after axon damage.
The contrast in regenerative potential between peripheral and central axonal branches of DRG neurons has long been a focus of neurological research, as it holds key insights for treating nerve injuries. Peripheral axons can self-regenerate to some extent after injury, enabling partial functional recovery, while central axons—such as those in the spinal cord—often fail to regrow, leading to permanent disabilities. This study addresses this disparity by zeroing in on DBNDD2, a previously less-studied protein whose expression patterns align closely with regenerative outcomes. After peripheral axon injury (modeled via sciatic nerve axotomy), DBNDD2 levels drop in DRGs, coinciding with the onset of regeneration. In contrast, central axon injury (via dorsal root axotomy) triggers an increase in DBNDD2, which correlates with regenerative failure. This inverse relationship between DBNDD2 expression and regeneration capacity strongly suggests the protein plays a inhibitory role in axon regrowth.
Developmental changes in DBNDD2 expression further support its regulatory role in axon regeneration. Neonatal mammals exhibit greater axon regenerative potential than adults, and this study found DBNDD2 levels are significantly lower in neonatal DRGs, rising steadily as rats mature into adults. This developmental upregulation of DBNDD2 parallels the gradual loss of regenerative capacity, reinforcing the idea that high DBNDD2 abundance in adults may suppress axon growth. Functional validation through DBNDD2 knockdown directly confirmed this hypothesis: reducing DBNDD2 levels reversed the limited regenerative ability of adult DRG neurons, promoting neurite outgrowth in cell models and enhancing axon regeneration in live adult rats after sciatic nerve crush. This not only confirms DBNDD2 as a negative regulator of regeneration but also demonstrates that targeting it can unlock latent regenerative potential in adult nervous systems.
Bioinformatic analyses expanded on these findings by identifying ESR1 as a key interacting partner of DBNDD2. ESR1, a transcription factor with known roles in cell growth and differentiation, showed an expression trend mirroring DBNDD2 after axon injury—down-regulated post-peripheral injury and up-regulated after central injury. The predicted interaction between ESR1 and DBNDD2, along with evidence that ESR1 may target DBNDD2, introduces a potential regulatory pathway underlying axon regeneration. This suggests ESR1 could modulate DBNDD2 expression to control regenerative outcomes, though further studies are needed to clarify the exact molecular mechanisms of this interaction, such as whether ESR1 directly binds to DBNDD2’s promoter region to regulate its transcription.
The implications of these findings extend beyond basic research, offering a clear therapeutic target for axon injury. Current treatments for nerve damage, such as surgery or physical therapy, often yield limited results, especially for central nervous system injuries. By suppressing DBNDD2—either through genetic knockdown, small-molecule inhibitors, or other targeted approaches—clinicians may be able to enhance axon regeneration in adult patients, improving functional recovery. The fact that DBNDD2 knockdown works in both neonatal and adult neurons also indicates its regulatory role is consistent across development, making it a versatile target for injuries occurring at different life stages. Additionally, the link between ESR1 and DBNDD2 opens avenues for combination therapies, where modulating ESR1 activity could indirectly reduce DBNDD2 levels, providing a more accessible approach than direct DBNDD2 targeting.
Overall, this research advances understanding of the molecular basis of axon regeneration, highlighting DBNDD2 as a critical inhibitory factor. By connecting DBNDD2 expression to regenerative success, identifying its developmental regulation, and uncovering its interaction with ESR1, the study lays the groundwork for novel therapies that can unlock the regenerative potential of adult mammalian neurons, offering hope for patients with previously untreatable axon injuries.
ＤＯＩ：10.1007/s11684-025-1146-2