Gene expression control, patterning and growth during appendage development
During animal development the organism cells restrict their developmental potential while acquire the different cell fates. These cells' responses depend on the extracellular cues they perceive and intrinsic factors they express and often require the precise modification of gene expression in both time and space. For example, appendage formation requires the activation of a set of genes that specifies a group of cells that will proliferate and pattern to generate the characteristic adult structure. Understanding the molecular mechanism underlying appendage specification, patterning and growth control is important not only for developmental biology but also to understand many diseases such as cancer or congenital malformations where this process is de-regulated. To provide insights into this general problem, we have been focusing on appendage development in the fruit fly, Drosophila melanogaster using genetic and molecular techniques.
Our research is centered in:
1-Deciphering the morphogenetic processes that control the development of appendages.
Joints allow the articulation of the legs, are precisely located along the proximo-Distal axis of the leg and depend on the Notch pathway for their formation. Our group have identified that the transcription factor dysfusion (dys) is expressed in response to Notch in the joints and that dys is absolutely required for joint development (Figure 1). Our objective is to understand how dys controls the morphogenetic events that sculpt a joint such as programed cell death and epitelial cell shape.
Figure 1: Loss of distal joints in dys mutant legs.
2-Studying the function of the transcription factors Sp1 and buttonhead (btd) during appendage development.
btd and Sp1btd and Sp1 play an important role specifying ventral vs dorsal appendage fate and regulating the growth of the leg. Also noteworthy is that the closest vertebrate homologs of Sp1, Sp8 and Sp9, which are also expressed in the limbs, are required for limb development in the mouse, probably due to an evolutionarily conserved role of these transcription factors. We have previously shown that mouse Sp8 is able to rescue some aspects of appendage development in Sp1 mutant embryos, suggesting that some of their functions have been conserved despite more than 500 million years of independent evolution. Our research is centered in identified Sp1/Btd downstream genes that direct the leg program and control the growth of this appendage.
3-Gene expression regulation during wing development.
Organ development, in our case the fly wing, required the subdivision in territories with different cell fates to generate the characteristic adult pattern. Our lab investigates how these decisions are made at a molecular level. For this purpose we study the regulatory sequences or enhancers (non-coding sequences that dictate when, where and how much a gene is going to be transcribed) of the dorsal identity gene apterous (ap) (Figure 2).
Figure 2: Subdivision of the wing imaginal disc in Dorsal and Ventral territories by the gene apterous (ap).
Figure 3: Molecular logic of appendage formation.
|Last name||Name||Laboratory||Ext.*||Professional category|
|Agudo Ríos||Clara||421||4436||clara.agudo(at)cbm.csic.es||Becario JAE Intro|
|Estella Sagrado||Carlos||415.5.1||4402||cestella(at)cbm.csic.es||E.Científicos Titulares de Organismos Públicos de Investigación|
|García López||Alejandra||421||4402||Estudiante TFG|
|Ruiz Losada||Mireya||421||4436||mireya.ruiz(at)cbm.csic.es||Titulado Sup. Actividades Tecn. y Prof.GP1 66%|
- Córdoba S, Estella C. The transcription factor Dysfusion promotes fold and joint morphogenesis through regulation of Rho1. PLoS Genet. 2018 Aug 6;14(8):e1007584. doi: 10.1371/journal.pgen.1007584. eCollection 2018 Aug.
- Requena D, Álvarez JA, Gabilondo H, Loker R, Mann RS and Estella C. Origins and specification of the Drosophila wing. Current Biology. 2017 Dec.
- Córdoba S, Requena D, Jory A, Saiz A, Estella C. The evolutionarily conserved transcription factor Sp1 controls appendage growth through Notch signaling. Development. 2016 Oct 1;143(19):3623-3631.
- Bieli D, Kanca O, Requena D, Hamaratoglu F, Gohl D, Schedl P, Affolter M, Slattery M, Müller M, Estella C. Establishment of a Developmental Compartment Requires Interactions between Three Synergistic Cis-regulatory Modules. PLoS Genet. 2015 Oct 15;11(10):e1005376.
- Córdoba S, Estella C, The bHLH-PAS transcription factor dysfusion regulates tarsal joint formation in response to Notch activity during drosophila leg development. PLoS Genet. 2014 Oct 16;10(10):e1004621.
- Estella, C., Voutev, R. and Richard S. Mann, A Dynamic Network of Morphogens and Transcription Factors Patterns the Fly Leg. In Serge Plaza and François Payre, editors: Current Topics in Developmental Biology, Vol. 98, Burlington: Academic Press, 2012, pp. 173-198.
- Estella, C. and Mann, R.S. Non-redundant selector and growth-promoting functions of two sister genes, buttonhead and Sp1, in Drosophila leg development. PLoS Genet. 2010 Jun 24;6(6):e1001001.
- Estella, C., McKay, D., and Mann, R.S. Direct integrations of Wingless, Decapentaplegic, and autoregulatory inputs into Distalless during Drosophila leg development. Dev. Cell, (2008) 14:86-96.
- Estella, C. and Mann, R.S. Logic of Wg and Dpp induction of distal and medial fates in the Drosophila leg. Development, (2008), 135:627-636.
- Estella C, Rieckhof G, Calleja M, Morata G. The role of buttonhead and Sp1 in the development of the ventral imaginal discs of Drosophila. Development. 2003 Dec;130(24):5929-41.
Richard Mann (Columbia University, NYC)
Markus Affolter (Biozentrum, Basel)
Matthew Slattery (Univ. of Minnesota, MN)
Jose Felix de Celis (CBMSO)
Antonio Baonza (CBMSO)