Project description:The distinct blend of molecular and cellular features that define neuronal subtype identity are central to shaping how individual subtypes impact animal behavior. The diversity of the mammalian nervous system is vast — the retina alone contains over 100 neuronal subtypes. Yet, the genetic processes giving rise to this stunning structural and functional diversity remain poorly understood. Here, we uncover a graded expression pattern of the transcription factor Brn3b that tunes and maintains multiple, subtype-defining transcriptional and morphophysiological features of the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). Disruption of this Brn3b gradient causes the transcriptional and morphophysiological identity of ipRGC subtypes to begin to converge, leading to dysfunction in multiple ipRGC-dependent behaviors. These findings show that a single transcription factor gradient can tune a diverse array of features to shape neuronal identity and circuit function to drive behavior.
Project description:The morphogen Indian Hedgehog plays a very important role during intestinal embryogenesis, but also maintains homeostasis in the adult gut. Intestinal Hedgehog is expressed by the intestinal epithelium and signals in paracrine manner to fibroblasts in the stromal compartment. We studied the colonic changes upon activation of the Hedgehog pathway by deleting the Hedgehog receptor Patched1 in order to alleviate its repressive function.
Project description:We report that Hedgehog signaling is a heterochronic pathway that determines the timing of the transition from specified cardiac progenitor to differentiated cardiomyocyte, a function distinct from its previously described roles affecting cellular patterning or proliferation. Hedgehog signaling was required to prevent premature differentiation and disruption of cardiac morphogenesis in vivo and the Hedgehog signaling transcription factor GLI1 was sufficient to delay differentiation in stem cell-derived cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro that inhibited the induction of the cardiac differentiation program. The GLI1-driven gene regulatory network is sufficient to induce Hedgehog-naive in vitro cardiac progenitors to adopt an epigenomic state reminiscent of second heart field cardiac progenitors in vivo. A Hh-dependent GLI transcription factor switch functions as a differentiation timer, restricting activity of the progenitor network to the second heart field and permitting cardiomyocyte differentiation in the heart. GLI1 expression is broadly associated with the progenitor state, and its activity also delayed the differentiation of specified neural progenitors in vitro. We posit that Hedgehog signaling functions as a heterochronic regulator that transiently maintains diverse progenitor populations for complex organ development and that may explain diverse Hedgehog signaling-dependent phenomena.
Project description:We report that Hedgehog signaling is a heterochronic pathway that determines the timing of the transition from specified cardiac progenitor to differentiated cardiomyocyte, a function distinct from its previously described roles affecting cellular patterning or proliferation. Hedgehog signaling was required to prevent premature differentiation and disruption of cardiac morphogenesis in vivo and the Hedgehog signaling transcription factor GLI1 was sufficient to delay differentiation in stem cell-derived cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro that inhibited the induction of the cardiac differentiation program. The GLI1-driven gene regulatory network is sufficient to induce Hedgehog-naive in vitro cardiac progenitors to adopt an epigenomic state reminiscent of second heart field cardiac progenitors in vivo. A Hh-dependent GLI transcription factor switch functions as a differentiation timer, restricting activity of the progenitor network to the second heart field and permitting cardiomyocyte differentiation in the heart. GLI1 expression is broadly associated with the progenitor state, and its activity also delayed the differentiation of specified neural progenitors in vitro. We posit that Hedgehog signaling functions as a heterochronic regulator that transiently maintains diverse progenitor populations for complex organ development and that may explain diverse Hedgehog signaling-dependent phenomena.
Project description:We report that Hedgehog signaling is a heterochronic pathway that determines the timing of the transition from specified cardiac progenitor to differentiated cardiomyocyte, a function distinct from its previously described roles affecting cellular patterning or proliferation. Hedgehog signaling was required to prevent premature differentiation and disruption of cardiac morphogenesis in vivo and the Hedgehog signaling transcription factor GLI1 was sufficient to delay differentiation in stem cell-derived cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro that inhibited the induction of the cardiac differentiation program. The GLI1-driven gene regulatory network is sufficient to induce Hedgehog-naive in vitro cardiac progenitors to adopt an epigenomic state reminiscent of second heart field cardiac progenitors in vivo. A Hh-dependent GLI transcription factor switch functions as a differentiation timer, restricting activity of the progenitor network to the second heart field and permitting cardiomyocyte differentiation in the heart. GLI1 expression is broadly associated with the progenitor state, and its activity also delayed the differentiation of specified neural progenitors in vitro. We posit that Hedgehog signaling functions as a heterochronic regulator that transiently maintains diverse progenitor populations for complex organ development and that may explain diverse Hedgehog signaling-dependent phenomena.
Project description:We report that Hedgehog signaling is a heterochronic pathway that determines the timing of the transition from specified cardiac progenitor to differentiated cardiomyocyte, a function distinct from its previously described roles affecting cellular patterning or proliferation. Hedgehog signaling was required to prevent premature differentiation and disruption of cardiac morphogenesis in vivo and the Hedgehog signaling transcription factor GLI1 was sufficient to delay differentiation in stem cell-derived cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro that inhibited the induction of the cardiac differentiation program. The GLI1-driven gene regulatory network is sufficient to induce Hedgehog-naive in vitro cardiac progenitors to adopt an epigenomic state reminiscent of second heart field cardiac progenitors in vivo. A Hh-dependent GLI transcription factor switch functions as a differentiation timer, restricting activity of the progenitor network to the second heart field and permitting cardiomyocyte differentiation in the heart. GLI1 expression is broadly associated with the progenitor state, and its activity also delayed the differentiation of specified neural progenitors in vitro. We posit that Hedgehog signaling functions as a heterochronic regulator that transiently maintains diverse progenitor populations for complex organ development and that may explain diverse Hedgehog signaling-dependent phenomena.