Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn
Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn
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DOI：
10.1242/dev.02167
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发表时间：
2005-12-01
期刊：
影响因子：
4.6
通讯作者：
Johnson, JE
中科院分区：
文献类型：
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作者：
Glasgow, SM;Henkel, RM;Johnson, JE
人和小鼠PTF1A/PTF1A基因的突变导致永久性糖尿病和小脑发育不全。我们表明，PTF1A存在于脊髓背角和小脑中GABA能神经元的前体中。 PTF1A中的无效突变揭示了其对背角GABA能神经元的要求。具体而言，PTF1A是生成早期出生（DI4，E10.5）和后期（DIL（A），E12.5）背侧神经元间种群LHX1/5和PAX2所确定的。此外，在没有PTF1A的情况下，DI4背上神经元转移至DI5（LMX1B+），将DIL（a）转移到DIL（B）（LMX1B+; TLX3（+））。神经元的这种错误指定导致抑制性GABA能神经元完全丧失，E16.5脊髓背角的兴奋性谷氨酸能神经元增加。因此，PTF1A功能对于发育中的脊髓中谷氨酸能神经元细胞的命运是GABA能至关重要的，并且在抑制性和兴奋性脑膜间发育之间提供了重要的遗传联系。
Mutations in the human and mouse PTF1A/Ptf1a genes result in permanent diabetes mellitus and cerebellar agenesis. We show that Ptf1a is present in precursors to GABAergic neurons in spinal cord dorsal horn as well as the cerebellum. A null mutation in Ptf1a reveals its requirement for the dorsal horn GABAergic neurons. Specifically, Ptf1a is required for the generation of early-born (dI4, E10.5) and late-born (dIL(A), E12.5) dorsal interneuron populations identified by homeodomain factors Lhx1/5 and Pax2. Furthermore, in the absence of Ptf1a, the dI4 dorsal interneurons trans-fate to dI5 (Lmx1b+), and the dIL(A) to dIL(B) (Lmx1b+;Tlx3(+)). This mis-specification of neurons results in a complete loss of inhibitory GABAergic neurons and an increase in the excitatory glutamatergic neurons in the dorsal horn of the spinal cord by E16.5. Thus, Ptf1a function is essential for GABAergic over glutamatergic neuronal cell fates in the developing spinal cord, and provides an important genetic link between inhibitory and excitatory interneuron development.