Project description:The vertebral column of individual mammalian species often exhibits remarkable robustness in the number and identity of vertebral elements that form (known as axial formulae). The genetic mechanism(s) underlying this constraint however remain ill-defined. Here, we reveal the interplay of three regulatory pathways (Gdf11, miR-196 and Retinoic acid) is essential in constraining total vertebral number and regional axial identity in the mouse, from cervical through to tail vertebrae. All three pathways have differing control over Hox cluster expression, with heterochronic and quantitative changes found to parallel changes in axial identity. However, our work reveals an additional role for Hox genes in supporting axial elongation within the tail region, providing important support for an emerging view that mammalian Hox function is not limited to imparting positional identity as the mammalian body plan is laid down. More broadly, this work provides a molecular framework to interrogate mechanisms of evolutionary change and congenital anomalies of the vertebral column.
Project description:The axial skeleton of individual mammalian species exhibits remarkable robustness in the number and identity of vertebral elements that form(Owen 1853; Owen 1866; Narita and Kuratani 2005). Between mammalian species however, a great diversity in axial formulae has arisen due to natural selection(Narita and Kuratani 2005; Thewissen et al. 2006; Buchholtz 2007; Matsubara et al. 2017; Kingsley et al. 2017). The genetic mechanism(s) by which axial formulae in mammals is canalised, or manipulated to drive this diversity, remains a major question in biology. Here, we reveal three regulatory pathways essential in constraining total vertebral number and regional axial identity in the mouse. Specifically, the manipulation of Gdf11, Retinoic acid and microRNA-196 activity, individually and cumulatively, led to increasing total vertebral number and allowed us to understand the molecular logic constraining each major division of the vertebral column, from cervical through to tail vertebrae. All three pathways had differing control over Hox cluster expression, with heterochronic and quantitative changes in Hox expression found to parallel changes in axial identity. However, our work revealed an additional, and highly unexpected, role for Hox genes in supporting axial elongation within the tail region. This provides important support for an emerging view that mammalian Hox gene function is not limited to imparting positional identity as the mammalian body plan is laid down, and more broadly, this work provides a molecular framework with which to interrogate mechanisms of evolutionary change.
Project description:The axial skeleton of individual mammalian species exhibits remarkable robustness in the number and identity of vertebral elements that form(Owen 1853; Owen 1866; Narita and Kuratani 2005). Between mammalian species however, a great diversity in axial formulae has arisen due to natural selection(Narita and Kuratani 2005; Thewissen et al. 2006; Buchholtz 2007; Matsubara et al. 2017; Kingsley et al. 2017). The genetic mechanism(s) by which axial formulae in mammals is canalised, or manipulated to drive this diversity, remains a major question in biology. Here, we reveal three regulatory pathways essential in constraining total vertebral number and regional axial identity in the mouse. Specifically, the manipulation of Gdf11, Retinoic acid and microRNA-196 activity, individually and cumulatively, led to increasing total vertebral number and allowed us to understand the molecular logic constraining each major division of the vertebral column, from cervical through to tail vertebrae. All three pathways had differing control over Hox cluster expression, with heterochronic and quantitative changes in Hox expression found to parallel changes in axial identity. However, our work revealed an additional, and highly unexpected, role for Hox genes in supporting axial elongation within the tail region. This provides important support for an emerging view that mammalian Hox gene function is not limited to imparting positional identity as the mammalian body plan is laid down, and more broadly, this work provides a molecular framework with which to interrogate mechanisms of evolutionary change.
