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They arise in the ventralmost progenitor domain of the rhombencephalon characterized by expression of the homeodomain transcription factors Nkx2.2 and Phox2b. Phox2b in particular plays a key role in the specification of branchiomotor neurons. In its absence, generic neuronal differentiation is defective in the progenitor domain and no branchiomotor neurons are produced. Conversely, ectopic expression of Phox2b in spinal regions of the neural tube promotes cell cycle exit and neuronal differentiation and, at the same time, induces genes and an axonal phenotype characteristic for branchiomotor neurons. How Phox2b exerts its pleiotropic functions, both as a proneural gene and a neuronal subtype determinant, has remained unknown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>To gain further insights into the genetic program downstream of Phox2b, we searched for novel Phox2b-regulated genes by cDNA microarray analysis of facial branchiomotor neuron precursors from heterozygous and homozygous <jats:italic>Phox2b<\/jats:italic> mutant embryos. We selected for functional studies the genes encoding the axonal growth promoter Gap43, the Wnt antagonist Sfrp1 and the transcriptional regulator Sox13, which were not previously suspected to play roles downstream of <jats:italic>Phox2b<\/jats:italic> and whose expression was affected by <jats:italic>Phox2b<\/jats:italic> misexpression in the spinal cord. While <jats:italic>Gap43<\/jats:italic> did not produce an obvious phenotype when overexpressed in the neural tube, <jats:italic>Sfrp1<\/jats:italic> induced the interneuron marker Lhx1,5 and <jats:italic>Sox13<\/jats:italic> inhibited neuronal differentiation. We then tested whether <jats:italic>Sfrp1<\/jats:italic> and <jats:italic>Sox13<\/jats:italic>, which are down-regulated by Phox2b in the facial neuron precursors, would antagonize some aspects of <jats:italic>Phox2b<\/jats:italic> activity. Co-expression of <jats:italic>Sfrp1<\/jats:italic> prevented <jats:italic>Phox2b<\/jats:italic> from repressing Lhx1,5 and alleviated the commissural axonal phenotype. When expressed together with <jats:italic>Sox13<\/jats:italic>, <jats:italic>Phox2b<\/jats:italic> was still able to promote cell cycle exit and neuronal differentiation, but the cells failed to relocate to the mantle layer and to extinguish the neural stem cell marker Sox2.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our results suggest novel roles for <jats:italic>Sfrp1<\/jats:italic> and <jats:italic>Sox13<\/jats:italic> in neuronal subtype specification and generic neuronal differentiation, respectively, and indicate that down-regulation of <jats:italic>Sfrp1<\/jats:italic> and <jats:italic>Sox13<\/jats:italic> are essential aspects of the genetic program controlled by Phox2b in cranial motoneurons.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/1749-8104-3-14","type":"journal-article","created":{"date-parts":[[2008,6,19]],"date-time":"2008-06-19T18:17:49Z","timestamp":1213899469000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Identification of Phox2b-regulated genes by expression profiling of cranial motoneuron precursors"],"prefix":"10.1186","volume":"3","author":[{"given":"Patrick","family":"Pla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Rose","family":"Hirsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Le Crom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Reiprich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent R","family":"Harley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christo","family":"Goridis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2008,6,19]]},"reference":[{"issue":"6","key":"46_CR1","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1101\/gad.255803","volume":"17","author":"A Pattyn","year":"2003","unstructured":"Pattyn A, Vallstedt A, Dias JM, Samad OA, Krumlauf R, Rijli FM, Brunet JF, Ericson J: Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. 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