Noggin null allele mice exhibit a microform of holoprosencephaly

Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin−/− mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin−/− mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin−/− mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HP

Fibroblast growth factor 10 is a negative regulator of postnatal neurogenesis in the mouse hypothalamus

New neurons are generated in the postnatal rodent hypothalamus, with a subset of tanycytes in the third ventricular (3V) wall serving as neural stem/progenitor cells. However, the precise stem cell niche organization, the intermediate steps and the endogenous regulators of postnatal hypothalamic neurogenesis remain elusive. Quantitative lineage-tracing in vivo revealed that conditional deletion of fibroblast growth factor 10 (Fgf10) from Fgf10-expressing beta-tanycytes at postnatal days (P)4-5 results in the generation of significantly more parenchymal cells by P28, composed mostly of ventromedial and dorsomedial neurons and some glial cells, which persist into adulthood. A closer scrutiny in vivo and ex vivo revealed that the 3V wall is not static and is amenable to cell movements. Furthermore, normally beta-tanycytes give rise to parenchymal cells via an intermediate population of alpha-tanycytes with transient amplifying cell characteristics. Loss of Fgf10 temporarily attenuates the amplification of beta-tanycytes but also appears to delay the exit of their alpha-tanycyte descendants from the germinal 3V wall. Our findings suggest that transience of cells through the alpha-tanycyte domain is a key feature, and Fgf10 is a negative regulator of postnatal hypothalamic neurogenesis.Peer reviewe

A molecular roadmap of the AGM region reveals BMP ER as a novel regulator of HSC maturation

In the developing embryo, hematopoietic stem cells (HSCs) emerge from the aorta-gonad-mesonephros (AGM) region, but the molecular regulation of this process is poorly understood. Recently, the progression from E9.5 to E10.5 and polarity along the dorso-ventral axis have been identified as clear demarcations of the supportive HSC niche. To identify novel secreted regulators of HSC maturation, we performed RNA sequencing over these spatiotemporal transitions in the AGM region and supportive OP9 cell line. Screening several proteins through an ex vivo reaggregate culture system, we identify BMP ER as a novel positive regulator of HSC development. We demonstrate that BMP ER is associated with BMP signaling inhibition, but is transcriptionally induced by BMP4, suggesting that BMP ER contributes to the precise control of BMP activity within the AGM region, enabling the maturation of HSCs within a BMP-negative environment. These findings and the availability of our transcriptional data through an accessible interface should provide insight into the maintenance and potential derivation of HSCs in culture.Peer reviewe

Mechanical Constraint from Growing Jaw Facilitates Mammalian Dental Diversity

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Fgf10-Expressing Tanycytes Add New Neurons to the Appetite/Energy-Balance Regulating Centers of the Postnatal and Adult Hypothalamus

Increasing evidence suggests that neurogenesis occurs in the postnatal and adult mammalian hypothalamus. However, the identity and location of the putative progenitor cells is under much debate, and little is known about the dynamics of neurogenesis in unchallenged brain. Previously, we postulated that Fibroblast growth factor 10-expressing (Fgf10�) tanycytes constitute a population of progenitor cells in the mouse hypothalamus. Here, we show that Fgf10� tanycytes express markers of neural stem/progenitor cells, divide late into postnatal life, and can generate both neurons and astrocytes in vivo. Stage-specific lineage-tracing of Fgf10� tanycytes using Fgf10- creERT2 mice, reveals robust neurogenesis at postnatal day 28 (P28), lasting as late as P60. Furthermore, we present evidence for amplification of Fgf10-lineage traced neural cells within the hypothalamic parenchyma itself. The neuronal descendants of Fgf10� tanycytes predominantly populate the arcuate nucleus, a subset ofwhichexpress the orexigenic neuronal marker, Neuropeptide-Y,andrespond to fastingandleptin-induced signaling.Thesestudiesprovidedirectevidenceinsupportofhypothalamicneurogenesisduringlate postnataland adult life, and identify Fgf10�tanycytes as a source of parenchymal neurons with putative roles in appetite and energy balance