Prdm13 Mediates the Balance of Inhibitory and Excitatory Neurons in Somatosensory Circuits

• Published in: Developmental cell Vol. 25; no. 2; pp. 182 - 195
• Main Authors: Chang, Joshua C., Meredith, David M., Mayer, Paul R., Borromeo, Mark D., Lai, Helen C., Ou, Yi-Hung, Johnson, Jane E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-04-2013
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blotting, Western; Cell Differentiation; Cells, Cultured; Chick Embryo; Chromatin Immunoprecipitation; DNA Primers - chemistry; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Female; Fluorescent Antibody Technique; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; In Situ Hybridization; Mice; Mice, Knockout; Neurons - cytology; Neurons - metabolism; PAX2 Transcription Factor - metabolism; RNA, Small Interfering - genetics; Spinal Cord - cytology; Spinal Cord - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Zinc Fingers
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.02.015

Generating a balanced network of inhibitory and excitatory neurons during development requires precise transcriptional control. In the dorsal spinal cord, Ptf1a, a basic helix-loop-helix (bHLH) transcription activator, maintains this delicate balance by inducing homeodomain (HD) transcription factors such as Pax2 to specify the inhibitory lineage while suppressing HD factors such as Tlx1/3 that specify the excitatory lineage. We uncover the mechanism by which Ptf1a represses excitatory cell fate in the inhibitory lineage. We identify Prdm13 as a direct target of Ptf1a and reveal that Prdm13 actively represses excitatory cell fate by binding to regulatory sequences near the Tlx1 and Tlx3 genes to silence their expression. Prdm13 acts through multiple mechanisms, including interactions with the bHLH factor Ascl1, to repress Ascl1 activation of Tlx3. Thus, Prdm13 is a key component of a highly coordinated transcriptional network that determines the balance of inhibitory versus excitatory neurons in the dorsal spinal cord.
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► Prdm13 is directly downstream of Ptf1a and is required for neuronal specification ► Prdm13 suppresses excitatory neuron fate in inhibitory neurons ► Prdm13 connects the activities of bHLH factors and homeodomain factors ► Opposing activities of Ascl1 and Prdm13 regulate glutamatergic specifiers Tlx1/3
Chang et al. find that inhibitory neurons in the spinal cord express the transcription factor Prdm13 downstream of Ptf1a. Prdm13 represses excitatory gene transcription and antagonizes the action of the transcription factor Ascl1 on its target excitatory genes, thus repressing the excitatory fate in inhibitory neurons.