Loss of Ptf1a Leads to a Widespread Cell-Fate Misspecification in the Brainstem, Affecting the Development of Somatosensory and Viscerosensory Nuclei.

Unlabelled: The brainstem contains diverse neuronal populations that regulate a wide range of processes vital to the organism. Proper cell-fate specification decisions are critical to achieve neuronal diversity in the CNS, but the mechanisms regulating cell-fate specification in the developing brainstem are poorly understood. Previously, it has been shown that basic helix-loop-helix transcription factor Ptf1a is required for the differentiation and survival of neurons of the inferior olivary and cochlear brainstem nuclei, which contribute to motor coordination and sound processing, respectively. In this study, we show that the loss of Ptf1a compromises the development of the nucleus of the solitary tract, which processes viscerosensory information, and the spinal and principal trigeminal nuclei, which integrate somatosensory information of the face. Combining genetic fate-mapping, birth-dating, and gene expression studies, we found that at least a subset of brainstem abnormalities in Ptf1a(-/-) mice are mediated by a dramatic cell-fate misspecification in rhombomeres 2-7, which results in the production of supernumerary viscerosensory and somatosensory neurons of the Lmx1b lineage at the expense of Pax2(+) GABAergic viscerosensory and somatosensory neurons, and inferior olivary neurons. Our data identify Ptf1a as a major regulator of cell-fate specification decisions in the developing brainstem, and as a previously unrecognized developmental regulator of both viscerosensory and somatosensory brainstem nuclei.

Significance Statement: Cell-fate specification decisions are critical for normal CNS development. Although extensively studied in the cerebellum and spinal cord, the mechanisms mediating cell-fate decisions in the brainstem, which regulates a wide range of processes vital to the organism, remain largely unknown. Here we identified mouse Ptf1a as a novel regulator of cell-fate decisions during both early and late brainstem neurogenesis, which are critical for proper development of several major classes of brainstem cells, including neurons of the somatosensory and viscerosensory nuclei. Since loss-of-function PTF1A mutations were described in human patients, we suggest Ptf1a-dependent cell-fate misspecification as a novel mechanism of human brainstem pathology.