Levanon Ditsa, Bettoun David, Harris-Cerruti Catherine, Woolf Eilon, Negreanu Varda, Eilam Raya, Bernstein Yael, Goldenberg Dalia, Xiao Cuiying, Fliegauf Manfred, Kremer Eitan, Otto Florian, Brenner Ori, Lev-Tov Aharon, Groner Yoram
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
EMBO J. 2002 Jul 1;21(13):3454-63. doi: 10.1093/emboj/cdf370.
The RUNX transcription factors are important regulators of linage-specific gene expression in major developmental pathways. Recently, we demonstrated that Runx3 is highly expressed in developing cranial and dorsal root ganglia (DRGs). Here we report that within the DRGs, Runx3 is specifically expressed in a subset of neurons, the tyrosine kinase receptor C (TrkC) proprioceptive neurons. We show that Runx3-deficient mice develop severe limb ataxia due to disruption of monosynaptic connectivity between intra spinal afferents and motoneurons. We demonstrate that the underlying cause of the defect is a loss of DRG proprioceptive neurons, reflected by a decreased number of TrkC-, parvalbumin- and beta-galactosidase-positive cells. Thus, Runx3 is a neurogenic TrkC neuron-specific transcription factor. In its absence, TrkC neurons in the DRG do not survive long enough to extend their axons toward target cells, resulting in lack of connectivity and ataxia. The data provide new genetic insights into the neurogenesis of DRGs and may help elucidate the molecular mechanisms underlying somatosensory-related ataxia in humans.
RUNX转录因子是主要发育途径中谱系特异性基因表达的重要调节因子。最近，我们证明Runx3在发育中的颅神经节和背根神经节（DRG）中高度表达。在此我们报告，在DRG内，Runx3在一部分神经元中特异性表达，即酪氨酸激酶受体C（TrkC）本体感觉神经元。我们发现，Runx3基因敲除小鼠由于脊髓内传入神经与运动神经元之间的单突触连接中断而出现严重的肢体共济失调。我们证明，该缺陷的根本原因是DRG本体感觉神经元的缺失，表现为TrkC、小白蛋白和β-半乳糖苷酶阳性细胞数量减少。因此，Runx3是一种神经源性TrkC神经元特异性转录因子。在其缺失的情况下，DRG中的TrkC神经元存活时间不足以将其轴突伸向靶细胞，导致连接缺失和共济失调。这些数据为DRG的神经发生提供了新的遗传学见解，并可能有助于阐明人类体感相关共济失调的分子机制。
