Marketa Kaucka Petersen

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The genetic and developmental basis of face formation & the evolution of facial diversity

The head is the most complex and sophisticated part of the vertebrate body. This body part hosts important and sensitive structures such as the brain and sensory organs, including the olfactory system (mediates olfaction), inner ear (is responsible for audition), eyes (account for vision), and others. These delicate structures require protection both during embryonic development and postnatally. Such protection is provided by the skull that has a complex 3D shape.

The frontal part of the skull is commonly referred to as "the face". Facial appearance relies mostly on the geometry of the underlying skeleton. An immense spectrum of facial shapes is found in the animal kingdom, allowing various lifestyles and a broad array of distinct feeding strategies. Additionally, humans possess an impressive variability of facial features underlying a person's individuality and use it for mutual recognition.

Two types of stiff matrix – cartilage and bone – contribute to the skeletal elements of the head. The evolution of the stiff matrix and the skull has been linked to the evolution of the centralized nervous system, the emergence of sensory organs, efficient feeding apparatus that allowed the shift from passive filter-feeding to the predatory lifestyle, and other evolutionary innovations. Apart from the evolutionary link, there is also a clear developmental link between the formation of the nervous system and the head's skeletal elements. A large part of human congenital syndromes affecting primarily the central nervous system is associated with some of the craniofacial malformations, ranging from minor facial asymmetries or morphometry changes, through cleft lip/palate, to severe conditions affecting breathing, feeding, or survival.

Previously, we have discovered that the original facial shape is established quite early during embryonic development and represented by chondrocranium – the cartilaginous template of the skull. It seems that the majority of signals instructing the formation of the chondrocranium originates within the developing nervous system at distinct time-points. Any morphological change of chondrocranium will be maintained even after the replacement by the bone, which highlights the role of chondrocranium in the formation of the facial shape.

The group "Craniofacial Biology" aims to reveal fundamental aspects of head formation and the genetic and developmental basis of facial variability. We focus on the identification of induction signals driving chondrogenesis, genomic regulation of gene expression, molecular mechanisms of the cell fate specification, conserved cell- and tissue-interactions (specifically, between nervous structures and facial ectomesenchyme), and their morphogenetic outcomes in various species (mouse, chick, zebrafish, Xenopus).

We combine methods such as single-cell -omics, genetic tracing, time- and tissue-specific gene modifications, viral transduction, live imaging, high-resolution imaging, micro-computed tomography, together with the classical spectrum of molecular and developmental biology methods to obtain a detailed understanding of evolution and development mechanisms of face-shaping.

1. Spatio-temporal (4D) mapping of the signaling centers inducing the skull formation

One of our goals is to uncover the 4D activity of signaling centers (also called organizers) that release the signals inducing the formation of the skeletal elements of the forming head during embryonic development. The sources of these inducing signals are mostly located within the developing nervous system. The distribution and the activity of the organizers are important for the formation of the complex skull geometry.

The candidate will investigate the spatio-temporal existence of signaling centers and the effect of major instructing signals they emit across several animal species (mouse, chicken, zebrafish, Xenopus, and others). This investigation will shed new light on the bone homology and the basis of facial variability in vertebrates. The candidate will combine publicly available transcriptomics data to uncover signals with the potential to induce the formation of cartilage or bone and use a combination of novel staining methods to map them in 4D (spatial organization during relevant developmental stages). Further functional validation will require tissue- and time-specific gene knockout performed in vivo (using Cre-based systems, CRISPR/Cas9, viral transduction, or application of chemical substances such as specific inhibitors or activators).

2. The effect of non-coding DNA sequences on the evolution of facial shapes

Enhancers are short DNA regions in the proximity of the start site of the respective gene and regulate its expression. These cis-acting elements have an essential role in the genetic regulatory networks. Their effect is often spatially-specific (for instance, the expression of Sonic Hedgehog is regulated by multiple enhancers during the development of mouse embryo, and 6 of them are active within the developing brain). The applicant will utilize scATACseq and publicly available databases to identify cis-regulatory elements for a specific set of genes that have a vital role in the skeletogenesis in the head. After the validation (e.g., 3C method and similar) of the specific promoter-enhancer interaction, the candidate will investigate the function of individual enhancers and their effect on the skull morphology using in vivo models.

In collaboration with Dr. Emma Rachel Andersson from Karolinska Institute (Stockholm, Sweden), we aim to utilize the NEPTUNE technique (neural plate targeting by intrauterine nano-injection) to modify gene expression or regulatory sequences in the developing nervous system of the mouse. This part of the project will involve in vivo work using mouse model, design and execution of various cloning strategies, viral transduction, whole-mount microscopy, 3D image reconstruction, micro-computed tomography, and other methods. Depending on the interests of the candidate, an international internship may be part of the project.

Collaborator: Dr. Emma R. Andersson, Karolinska Institute (Stockholm, Sweden)

3. Evolution of gene regulatory networks driving the skeletogenesis

The project is focused on the analysis and comparison of gene regulatory networks driving the formation of cartilage and bone in distant species. The essential data will be generated using single-cell RNA sequencing of defined areas and relevant developmental stages.

Ideally, the candidate driving this project should have an overview and good understanding of the currently available single-cell –omics methods, be skilled in R/python and possess a knowledge of basic statistical methods. Previous experience with analysis of the single-cell RNAseq datasets is an asset.

4. Ex vivo/embryoid-based methods as a flexible system to study the head formation

More than one-third of all congenital abnormalities are represented by some craniofacial malformation, ranging from relatively mild facial features or symmetry changes, through the cleft lip or cleft palate craniosynostoses to very severe conditions affecting feeding, breathing, and overall survival. Interestingly, human craniofacial syndromes are often accompanied by other symptoms or disorders affecting the central nervous system or the sensory organs. This association supports the link between the development of the nervous system and the formation of chondrocranium. The applicant will use publicly available databases (e.g., the single-cell atlas of developing mouse brain), communication with our collaborators in the clinics, and literature search to form a list of candidate genes that connect the development of the nervous system to the emergence of chondrocranium. A combination of some of the following methods will be used for subsequent validation:

  • Cell biology, in vitro techniques, microscopy (confocal, live-imaging), a spectrum of staining methods.
  • Micro/Nano-Computed tomography, segmentation, morphometrics, tissue contrasting.
  • Viral transduction, CRISPR/Cas9 technology, NEPTUNE technique
  • Search using single-cell –omics databases
  • In vivo work (mouse, chicken), targeted application of active compounds, transfection.
  • Cre-based strategies for targeted gene modifications (tissue- or time-specific) in the mouse.

We offer stimulating and friendly environment, interdisciplinary expertise, state-of-the-art techniques (genetic tracing, CRISPR/Cas9 knockouts performed in house, novel staining methods, broad spectrum of sequencing possibilities, bioinformatical support etc), various animal models, support in developing own ideas, frequent discussions and being a valuable part of an international team.

For more information on our research directions:

  1. Spatiotemporal structure of cell fate decisions in murine neural crest. Science, 2019
  2. Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage. eLife 2018
  3. Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage. eLife 2017
  4. Analysis of neural crest-derived clones reveals novel aspects of facial development. Science Advances 2016.

Review: Evolution and development of the cartilaginous skull: From a lancelet towards a human face. SCDB, 2019,

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