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Article ; Online: Computational modeling of TGF-β2:TβRI:TβRII receptor complex assembly as mediated by the TGF-β coreceptor betaglycan.

Madamanchi, Aasakiran / Ingle, Michelle / Hinck, Andrew P / Umulis, David M

2023 Volume 122, Issue 7, Page(s) 1342–1354

Abstract: Transforming growth factor-β1, -β2, and -β3 (TGF-β1, -β2, and -β3) are secreted signaling ligands that play essential roles in tissue development, tissue maintenance, immune response, and wound healing. TGF-β ligands form homodimers and signal by ... ...

Abstract	Transforming growth factor-β1, -β2, and -β3 (TGF-β1, -β2, and -β3) are secreted signaling ligands that play essential roles in tissue development, tissue maintenance, immune response, and wound healing. TGF-β ligands form homodimers and signal by assembling a heterotetrameric receptor complex comprised of two type I receptor (TβRI):type II receptor (TβRII) pairs. TGF-β1 and TGF-β3 ligands signal with high potency due to their high affinity for TβRII, which engenders high-affinity binding of TβRI through a composite TGF-β:TβRII binding interface. However, TGF-β2 binds TβRII 200-500 more weakly than TGF-β1 and TGF-β3 and signals with lower potency compared with these ligands. Remarkably, the presence of an additional membrane-bound coreceptor, known as betaglycan, increases TGF-β2 signaling potency to levels similar to TGF-β1 and -β3. The mediating effect of betaglycan occurs even though it is displaced from and not present in the heterotetrameric receptor complex through which TGF-β2 signals. Published biophysics studies have experimentally established the kinetic rates of the individual ligand-receptor and receptor-receptor interactions that initiate heterotetrameric receptor complex assembly and signaling in the TGF-β system; however, current experimental approaches are not able to directly measure kinetic rates for the intermediate and latter steps of assembly. To characterize these steps in the TGF-β system and determine the mechanism of betaglycan in the potentiation of TGF-β2 signaling, we developed deterministic computational models with different modes of betaglycan binding and varying cooperativity between receptor subtypes. The models identified conditions for selective enhancement of TGF-β2 signaling. The models provide support for additional receptor binding cooperativity that has been hypothesized but not evaluated in the literature. The models further showed that betaglycan binding to the TGF-β2 ligand through two domains provides an effective mechanism for transfer to the signaling receptors that has been tuned to efficiently promote assembly of the TGF-β2(TβRII)
MeSH term(s)	Transforming Growth Factor beta1 ; Transforming Growth Factor beta ; Transforming Growth Factor beta2 ; Transforming Growth Factor beta3 ; Ligands ; Protein Serine-Threonine Kinases/metabolism ; Computer Simulation
Chemical Substances	betaglycan (145170-29-2) ; Transforming Growth Factor beta1 ; Transforming Growth Factor beta ; Transforming Growth Factor beta2 ; Transforming Growth Factor beta3 ; Ligands ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2023.02.030
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Article ; Online: Early radial positional information in the cochlea is optimized by a precise linear BMP gradient and enhanced by SOX2.

Thompson, Matthew J / Young, Caryl A / Munnamalai, Vidhya / Umulis, David M

Scientific reports

2023 Volume 13, Issue 1, Page(s) 8567

Abstract: Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of hair cells and supporting ... ...

Abstract	Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of hair cells and supporting cells. This requires precision in the morphogen signals that set the initial radial compartment boundaries, but this has not been investigated. To measure gradient formation and morphogenetic precision in developing cochlea, we developed a quantitative image analysis procedure measuring SOX2 and pSMAD1/5/9 profiles in mouse embryos at embryonic day (E)12.5, E13.5, and E14.5. Intriguingly, we found that the pSMAD1/5/9 profile forms a linear gradient up to the medial ~ 75% of the PSD from the pSMAD1/5/9 peak in the lateral edge during E12.5 and E13.5. This is a surprising activity readout for a diffusive BMP4 ligand secreted from a tightly constrained lateral region since morphogens typically form exponential or power-law gradient shapes. This is meaningful for gradient interpretation because while linear profiles offer the theoretically highest information content and distributed precision for patterning, a linear morphogen gradient has not yet been observed. Furthermore, this is unique to the cochlear epithelium as the pSMAD1/5/9 gradient is exponential in the surrounding mesenchyme. In addition to the information-optimized linear profile, we found that while pSMAD1/5/9 is stable during this timeframe, an accompanying gradient of SOX2 shifts dynamically. Last, through joint decoding maps of pSMAD1/5/9 and SOX2, we see that there is a high-fidelity mapping between signaling activity and position in the regions that will become Kölliker's organ and the organ of Corti. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain.
MeSH term(s)	Mice ; Animals ; Cochlea ; Hair Cells, Auditory ; Signal Transduction ; Morphogenesis ; Gene Expression Regulation, Developmental ; Cell Differentiation
Language	English
Publishing date	2023-05-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-34725-4
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Article: Optimal Performance Objectives in the Highly Conserved Bone Morphogenetic Protein Signaling Pathway.

Shaikh, Razeen / Larson, Nissa J / Hanjaya-Putra, Donny / Zartman, Jeremiah / Umulis, David M / Li, Linlin / Reeves, Gregory T

bioRxiv : the preprint server for biology

2024

Abstract: Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in these ... ...

Abstract	Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in these cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant. For instance, some cellular systems require a rapid response, while others require high noise filtering. In this paper, we examine how the BMP- Smad pathway balances trade-offs among three such systems-level behaviors, or "Performance Objectives (POs)": response speed, noise amplification, and the sensitivity of pathway output to receptor input. Using a Smad pathway model fit to human cell data, we show that varying non-conserved parameters (NCPs) such as protein concentrations, the Smad pathway can be tuned to emphasize any of the three POs and that the concentration of nuclear phosphatase has the greatest effect on tuning the POs. However, due to competition among the POs, the pathway cannot simultaneously optimize all three, but at best must balance trade-offs among the POs. We applied the multi-objective optimization concept of the Pareto Front, a widely used concept in economics to identify optimal trade-offs among various requirements. We show that the BMP pathway efficiently balances competing POs across species and is largely Pareto optimal. Our findings reveal that varying the concentration of NCPs allows the Smad signaling pathway to generate a diverse range of POs. This insight identifies how signaling pathways can be optimally tuned for each context.
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.01.578451
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Article ; Online: Diversity and robustness of bone morphogenetic protein pattern formation.

Madamanchi, Aasakiran / Mullins, Mary C / Umulis, David M

Development (Cambridge, England)

2021 Volume 148, Issue 7

Abstract: Pattern formation by bone morphogenetic proteins (BMPs) demonstrates remarkable plasticity and utility in several contexts, such as early embryonic development, tissue patterning and the maintenance of stem cell niches. BMPs pattern tissues over many ... ...

Abstract	Pattern formation by bone morphogenetic proteins (BMPs) demonstrates remarkable plasticity and utility in several contexts, such as early embryonic development, tissue patterning and the maintenance of stem cell niches. BMPs pattern tissues over many temporal and spatial scales: BMP gradients as short as 1-2 cell diameters maintain the stem cell niche of the
MeSH term(s)	Animals ; Body Patterning/genetics ; Body Patterning/physiology ; Bone Development ; Bone Morphogenetic Proteins/genetics ; Bone Morphogenetic Proteins/metabolism ; Bone and Bones ; Drosophila/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Embryo, Nonmammalian/metabolism ; Embryonic Development ; Gene Expression Regulation, Developmental ; Signal Transduction ; Xenopus laevis/embryology ; Xenopus laevis/metabolism ; Zebrafish/embryology ; Zebrafish/metabolism ; Zebrafish Proteins
Chemical Substances	Bone Morphogenetic Proteins ; Drosophila Proteins ; Zebrafish Proteins
Language	English
Publishing date	2021-04-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.192344
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Article ; Online: Scale invariance of BMP signaling gradients in zebrafish.

Huang, Yan / Umulis, David M

Scientific reports

2019 Volume 9, Issue 1, Page(s) 5440

Abstract: In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates ... ...

Abstract	In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk. We quantified the BMP signaling gradient in wild-type and perturbed embryos and found that the system scales for reductions in cross-sectional perimeter of up to 30%. Furthermore, we found that the degree of scaling for intraspecies scaling within zebrafish is greater than that between Danioninae species.
MeSH term(s)	Animals ; Body Patterning ; Bone Morphogenetic Proteins/metabolism ; Embryo, Nonmammalian/metabolism ; Morphogenesis ; Signal Transduction ; Zebrafish/embryology ; Zebrafish/metabolism ; Zebrafish Proteins/metabolism
Chemical Substances	Bone Morphogenetic Proteins ; Zebrafish Proteins
Language	English
Publishing date	2019-04-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-41840-8
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Article ; Online: Mechanisms and Measurements of Scale Invariance of Morphogen Gradients.

Huang, Yan / Umulis, David

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1863, Page(s) 251–262

Abstract: Morphogen gradients provide positional information to underlying cells that translate the information into differential gene expression and eventually different cell fates. Scale invariance is the property where the gradients of the morphogen adjust ... ...

Abstract	Morphogen gradients provide positional information to underlying cells that translate the information into differential gene expression and eventually different cell fates. Scale invariance is the property where the gradients of the morphogen adjust proportionately to the size of the domain. Scale invariance of morphogen gradients or patterns of differentiation is a common phenomenon observed between individuals within the same species and between homologous tissues or structures in different species. To determine whether or not a pattern is scale invariant, others and we have developed definitions and measurements of gradient scaling. These include point-wise and global scaling errors as well as global scaling power. Furthermore, there are a number of mathematical conditions for scale invariance of advection-diffusion-reaction models that inform mechanisms of scaling. Herein we provide a deeper perspective on modeling and measurement of scale invariance of morphogen gradients.
MeSH term(s)	Algorithms ; Animals ; Biological Transport ; Diffusion ; Embryonic Development ; Intercellular Signaling Peptides and Proteins/metabolism ; Models, Theoretical ; Morphogenesis ; Signal Transduction
Chemical Substances	Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2018-10-15
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-8772-6_14
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Article: PDE-constrained shape registration to characterize biological growth and morphogenesis from imaging data.

Pawar, Aishwarya / Li, Linlin / Gosain, Arun K / Umulis, David M / Tepole, Adrian Buganza

Engineering with computers

2022 Volume 38, Issue 5, Page(s) 3909–3924

Abstract: We propose a PDE-constrained shape registration algorithm that captures the deformation and growth of biological tissue from imaging data. Shape registration is the process of evaluating optimum alignment between pairs of geometries through a spatial ... ...

Abstract	We propose a PDE-constrained shape registration algorithm that captures the deformation and growth of biological tissue from imaging data. Shape registration is the process of evaluating optimum alignment between pairs of geometries through a spatial transformation function. We start from our previously reported work, which uses 3D tensor product B-spline basis functions to interpolate 3D space. Here, the movement of the B-spline control points, composed with an implicit function describing the shape of the tissue, yields the total deformation gradient field. The deformation gradient is then split into growth and elastic contributions. The growth tensor captures addition of mass, i.e. growth, and evolves according to a constitutive equation which is usually a function of the elastic deformation. Stress is generated in the material due to the elastic component of the deformation alone. The result of the registration is obtained by minimizing a total energy functional which includes: a distance measure reflecting similarity between the shapes, and the total elastic energy accounting for the growth of the tissue. We apply the proposed shape registration framework to study zebrafish embryo epiboly process and tissue expansion during skin reconstruction surgery. We anticipate that our PDE-constrained shape registration method will improve our understanding of biological and medical problems in which tissues undergo extreme deformations over time.
Language	English
Publishing date	2022-07-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1459031-1
ISSN	1435-5663 ; 0177-0667
ISSN (online)	1435-5663
ISSN	0177-0667
DOI	10.1007/s00366-022-01682-x
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Article ; Online: "I Think I Am Getting There" Understanding the Computational Identity of Engineering Students Participating in a Computationally Intensive Thermodynamics Course.

Shoaib, Huma / Madamanchi, Aasakiran / Pienaar, Elsje / Umulis, David M / Cardella, Monica E

Biomedical engineering education

2022 Volume 3, Issue 1, Page(s) 1–21

Abstract: In response to the growing computational intensity of the healthcare industry, biomedical engineering (BME) undergraduate education is placing increased emphasis on computation. The presence of substantial gender disparities in many computationally ... ...

Abstract	In response to the growing computational intensity of the healthcare industry, biomedical engineering (BME) undergraduate education is placing increased emphasis on computation. The presence of substantial gender disparities in many computationally intensive disciplines suggests that the adoption of computational instruction approaches that lack intentionality may exacerbate gender disparities. Educational research suggests that the development of an engineering and computational identity is one factor that can support students' decisions to enter and persist in an engineering major. Discipline-based identity research is used as a lens to understand retention and persistence of students in engineering. Our specific purpose is to apply discipline-based identity research to define and explore the computational identities of undergraduate engineering students who engage in computational environments. This work will inform future studies regarding retention and persistence of students who engage in computational courses. Twenty-eight undergraduate engineering students (20 women, 8 men) from three engineering majors (biomedical engineering, agricultural engineering, and biological engineering) participated in semi-structured interviews. The students discussed their experiences in a computationally-intensive thermodynamics course offered jointly by the Biomedical Engineering and Agricultural & Biological Engineering departments. The transcribed interviews were analyzed through thematic coding. The gender stereotypes associated with computer programming also come part and parcel with computer programming, possibly threatening a student's sense of belonging in engineering. The majority of the participants reported that their computational identity was "in the making." Students' responses also suggested that their engineering identity and their computational identity were in congruence, while some incongruence is found between their engineering identity and a creative identity as well as between computational identity and perceived feminine norms. Responses also indicate that students associate specific skills with having a computational identity. This study's findings present an emergent thematic definition of a computational person constructed from student perceptions and experiences. Instructors can support students' nascent computational identities through intentional mitigation of the gender stereotypes and biases, and by framing assignments to focus on developing specific skills associated with the computational modeling processes.
Language	English
Publishing date	2022-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	3040682-1
ISSN	2730-5945 ; 2730-5937
ISSN (online)	2730-5945
ISSN	2730-5937
DOI	10.1007/s43683-022-00084-1
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Article ; Online: Scale invariance of BMP signaling gradients in zebrafish

Yan Huang / David M Umulis

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both ... ...

Abstract	Abstract In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk. We quantified the BMP signaling gradient in wild-type and perturbed embryos and found that the system scales for reductions in cross-sectional perimeter of up to 30%. Furthermore, we found that the degree of scaling for intraspecies scaling within zebrafish is greater than that between Danioninae species.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early radial positional information in the cochlea is optimized by a precise linear BMP gradient and enhanced by SOX2

Matthew J. Thompson / Caryl A. Young / Vidhya Munnamalai / David M. Umulis

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 14

Abstract: Abstract Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of hair cells and ... ...

Abstract	Abstract Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of hair cells and supporting cells. This requires precision in the morphogen signals that set the initial radial compartment boundaries, but this has not been investigated. To measure gradient formation and morphogenetic precision in developing cochlea, we developed a quantitative image analysis procedure measuring SOX2 and pSMAD1/5/9 profiles in mouse embryos at embryonic day (E)12.5, E13.5, and E14.5. Intriguingly, we found that the pSMAD1/5/9 profile forms a linear gradient up to the medial ~ 75% of the PSD from the pSMAD1/5/9 peak in the lateral edge during E12.5 and E13.5. This is a surprising activity readout for a diffusive BMP4 ligand secreted from a tightly constrained lateral region since morphogens typically form exponential or power-law gradient shapes. This is meaningful for gradient interpretation because while linear profiles offer the theoretically highest information content and distributed precision for patterning, a linear morphogen gradient has not yet been observed. Furthermore, this is unique to the cochlear epithelium as the pSMAD1/5/9 gradient is exponential in the surrounding mesenchyme. In addition to the information-optimized linear profile, we found that while pSMAD1/5/9 is stable during this timeframe, an accompanying gradient of SOX2 shifts dynamically. Last, through joint decoding maps of pSMAD1/5/9 and SOX2, we see that there is a high-fidelity mapping between signaling activity and position in the regions that will become Kölliker’s organ and the organ of Corti. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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