Infoscience

Thesis

From the early steps of whisker formation to its evolutionary disappearance: the (curious) case of Prdm1 and its regulation

Whiskers (also known as vibrissae) are sensory organs that are thought to have first appeared in Therapsida, a group of synapsids that includes mammals and evolutionary ancestors like the Thrinaxodon(1). They are highly conserved among mammals to the notable exception of the higher primates and are important for behavior, especially for nocturnal animals and the ones living in burrows(2). Furthermore, the mechanoreceptors of the vibrissae signal to the primary somatosensory cortex, where a discrete and well-defined structure in layer 4 represents each whisker(3). This structure, known as barrel cortex, occupies a large portion of the rodent brain. Strikingly, Prdm1 conditional KO (cKO) mice are one of the rare transgenic strains that do not develop whiskers while forming a pelage; on the other hand, the other head structures expressing Prdm1 (including pelage hair follicles and teeth) grow normally(4). In the developing whisker pad, Prdm1 expression is confined to the mesenchyme underlying the embryonic epidermis that will later form the whisker epidermal placode; it lasts until dermal papilla formation, when a “switch” occurs to the precursors of the inner root sheath. The Prdm1 ablation study we conducted revealed the absence of the patterned up-regulation of Bmp2 (marker of placode formation), Shh (a protein secreted by the epidermal placode responsible for the first epidermal signal) and Bmp4 (expressed in the pre-follicle mesenchyme). On the other hand, Lef1 is expressed uniformly in the mesenchyme of the whisker pad, thus pointing out the integrity of the βCatenin-mediated first mesenchymal signal. Those results suggest the role of Prdm1 as a master gene in whisker development. Prdm1 expressing cells are mainly non-proliferative; however, a small subpopulation at the periphery is cycling. Being Sox2 coexpressed with Prdm1 in the whisker mesenchyme, we performed lineage tracing with Sox2CreERT2 and ROSAYFP transgenic strains. Those experiments revealed that Sox2/Prdm1 expressing cells contribute to the formation of the dermal papilla, dermal sheath and putative pericytes of the whisker follicle and thus constitute a population of embryonic progenitors crucial for whisker formation. We subsequently investigated the development of the barrel cortex in our cKO mice. Intriguingly, a disorganized pattern was observed in cKO mice, suggesting that the loss of expression of a single gene, and consequently the disappearance of vibrissae, drastically impacts the development of the whole somatosensory system. Finally, we hypothesized that the loss of Prdm1 expression might explain the disappearance of whisker follicles in the human during evolution. Prdm1 being no longer expressed in the human lineage during hair follicle development(5), we reasoned that the loss of regulatory elements of its upstream genes might contribute to this phenomenon; we demonstrated that Lef1 acts upstream of Prdm1 during whisker development and are currently testing the role of its potential enhancers (Leaf) during this process. Bibliography: 1: (http://en.wikipedia.org/wiki/therapsid) 2: Petersen, C. C. H. The Functional Organization of the Barrel Cortex. Neuron 56, 339–355 (2007) 3: Woolsey, T. A. & Van der Loos, H. The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res. 17, 205–242 (1970) 4: Robertson, E. J. et al. Blimp1 regulates development of the posterior forelimb, caudal pharyngeal arches, heart and sensory vibrissae in mice. Development 134, 4335–4345 (2007). 5: Sellheyer, K. & Krahl, D. Blimp-1: a marker of terminal differentiation but not of sebocytic progenitor cells. J. Cutan. Pathol. 37, 362–370 (2010).

    Keywords: whisker ; evolution ; Prdm1 ; Lef1 ; barrel cortex ; primate-specific deletion

    Thèse École polytechnique fédérale de Lausanne EPFL, n° 6984 (2016)
    Programme doctoral Biotechnologie et Génie biologique
    Faculté des sciences de la vie
    Institut interfacultaire de Bioingénierie (SV)
    Laboratoire de dynamique des cellules souches
    Jury: Prof. Matteo Dal Peraro (président) ; Prof. Yann Barrandon (directeur de thèse) ; Prof. Denis Duboule, Prof. Giulio Cossu, Dr Javier Lopez-Rios (rapporteurs)

    Public defense: 2016-5-20

    Reference

    Record created on 2016-05-18, modified on 2016-08-25

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