The focus of my current research is to understand mechanisms of cellular signaling at the level of the primary cilia, and its relevance to human health and disease. My interests in ciliary signaling began when I was a graduate student at Brandeis with Dr. Piali Sengupta. I utilized C. elegans to study the mechanisms that determine the distinctive ciliary morphology of their sensory neurons. In my postdoctoral years in Dr. Peter Jackson’s lab at Genentech, using high-confidence proteomic approaches, I discovered the role of tubby family protein TULP3 in trafficking of GPCRs to cilia by coupling to the ciliary intraflagellar complex-A (IFT-A). I also identified an orphan GPCR, GPR161 that acts as a negative regulator of Sonic hedgehog (Shh) signaling during neural tube development via cAMP signaling by dynamically localizing to cilia.
My laboratory has made numerous contributions to the field of ciliary trafficking and signaling. We have now established tubby family proteins, TULP3 and Tubby as critical determinants for trafficking of almost all known rhodopsin family GPCRs to cilia. By extending the repertoire of Tulp3-dependent ciliary cargoes to include (a) Polycystins and Fibrocystin, proteins implicated in polycystic kidney disease (PKD), and (b) ARL13B, an atypical small GTPase linked to renal cystogenesis and trafficking lipidated cargoes, we have identified the predominant mechanism for trafficking of multiple types of membrane proteins to cilia. We have also demonstrated that embryonic stage nephron-specific Tulp3 knockout mice develop cystic kidneys, while retaining intact cilia. TULP3 and the brain-specific Tubby have now been established as the central players for trafficking multiple membrane-bound cargoes into mammalian cilia.
In parallel, we have been in the forefront of understanding the complex role of primary cilium-generated signaling, particularly that of negative regulation by GPR161, in the Shh pathway. We have also recently discovered that the MYND domain protein ANKMY2 serves as a critical negative regulator of Shh pathway during neural tube development by trafficking multiple adenylyl cyclases to cilia. Our discovery of GPR161 as a moderately strong repressor of the Shh pathway, and our ability to study cilium-generated signaling have unraveled new phenotypes arising from derepression of Shh signaling in multiple developmental paradigms. In collaboration with Dr. Richard Finnell, we have detected GPR161 mutations in patients suffering from neural tube defects (Hum Mol Gen, 2018, 28, 200-208). Others have linked germ line GPR161 mutations in human patients with predisposition to Shh-subtype medulloblastoma at rates similar to loss of Shh receptor PTCH1 (J Clin Oncol 2020, 38, 43-50).
Overall, our expertise in Shh signaling and its regulation by cilia, our demonstrated strengths in utilizing a multi-pronged approach including proteomics, cell biology, and reverse genetics to discover novel Shh pathway regulators, including the discovery of the Tulp3-Gpr161-Ankmy2 axis, and further engineering of conditional knock out and knock in alleles targeting these factors, uniquely position us to determine the role of basal suppression of Shh signaling in these diverse processes. Finally, the collaborative nature of research and the strong focus on translational biomedical research at UT Southwestern is instrumental for studying these diverse developmental paradigms aiming at understanding the role of primary cilia in development and disease.
- (1998), Medicine
- Medical School
- Banaras Hindu University (2002), Medicine
- Graduate School
- Brandeis University (2008), Biology
- Cilia organized signaling pathways
- Cilia specific signals in PKD
- Ciliary regulation of limb and skeletal development
- Ciliary signaling in neural tube development and disease
- Cilium-centrosome complex in Shh-medulloblastoma pathogenesis
- Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis.
- Walker RV, Maranto A, Palicharla VR, Hwang SH, Mukhopadhyay S, Qian F, Front Mol Biosci 2022 9 936070
- Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner.
- Hwang SH, Somatilaka BN, White K, Mukhopadhyay S, Elife 2021 Aug 10
- Interactions between TULP3 tubby domain cargo site and ARL13B amphipathic helix promote lipidated protein transport to cilia.
- Palicharla, V., Hwang, S., Somatilaka, B., Badgandi, H. B., Legue, E, Shimada, I, Tran, V., Woodruff, J., Liem, K, and Mukhopadhyay, S. BioRxiv 2021 Posted May 25, 2021 doi.org/10.1101/2021.05.25.445488 Preprint
- Ankmy2 Prevents Smoothened-Independent Hyperactivation of the Hedgehog Pathway via Cilia-Regulated Adenylyl Cyclase Signaling.
- Somatilaka BN, Hwang SH, Palicharla VR, White KA, Badgandi H, Shelton JM, Mukhopadhyay S, Dev. Cell 2020 Jul
- Developmental and regenerative paradigms of cilia regulated hedgehog signaling.
- Kopinke D, Norris AM, Mukhopadhyay S, Semin. Cell Dev. Biol. 2020 Jun
- Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities.
- Shimada IS, Somatilaka BN, Hwang SH, Anderson AG, Shelton JM, Rajaram V, Konopka G, Mukhopadhyay S Dev. Biol. 2019 Mar
- Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia.
- Hwang SH, Somatilaka BN, Badgandi H, Palicharla VR, Walker R, Shelton JM, Qian F, Mukhopadhyay S Curr. Biol. 2019 Feb
- Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
- Shimada IS, Hwang SH, Somatilaka BN, Wang X, Skowron P, Kim J, Kim M, Shelton JM, Rajaram V, Xuan Z, Taylor MD, Mukhopadhyay S Cell Rep 2018 Jan 22 5 1169-1184
- The G-protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner.
- Hwang SH, White KA, Somatilaka BN, Shelton JM, Richardson JA, Mukhopadhyay S Development 2017 Dec
- Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins.
- Badgandi HB, Hwang SH, Shimada IS, Loriot E, Mukhopadhyay S J. Cell Biol. 2017 Feb
Honors & Awards
- Alex Lemonade Stand Foundation A-grant awardee
- W.W. Caruth, Jr. Scholar in Biomedical Research
Endowed scholar, UT Southwestern (2013)
- CPRIT Scholar in Cancer Research
- Member, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center. (2013)
- American Society for Cell Biology. (2005)