Saikat Mukhopadhyay, M.D., Ph.D.
Associate Professor
Endowed Title W.W. Caruth, Jr. Scholar in Biomedical Research
School Medical School
Department Cell Biology
Graduate Programs Cancer Biology, Genetics, Development and Disease
Biography
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.
Education
- Undergraduate
- (1998), Medicine
- Medical School
- Banaras Hindu University (2002), Medicine
- Graduate School
- Brandeis University (2008), Biology
Research Interest
- 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
Publications
Featured Publications
- GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.
- Hoppe N, Harrison S, Hwang SH, Chen Z, Karelina M, Deshpande I, Suomivuori CM, Palicharla VR, Berry SP, Tschaikner P, Regele D, Covey DF, Stefan E, Marks DS, Reiter JF, Dror RO, Evers AS, Mukhopadhyay S, Manglik A, Nat Struct Mol Biol 2024 Feb
- Permanent deconstruction of intracellular primary cilia in differentiating granule cell neurons.
- Ott CM, Constable S, Nguyen TM, White K, Lee WA, Lippincott-Schwartz J, Mukhopadhyay S, bioRxiv 2023 Dec
- Context-dependent ciliary regulation of hedgehog pathway repression in tissue morphogenesis.
- Hwang SH, White KA, Somatilaka BN, Wang B, Mukhopadhyay S, PLoS Genet 2023 Nov 19 11 e1011028
- Human IFT-A complex structures provide molecular insights into ciliary transport.
- Jiang M, Palicharla VR, Miller D, Hwang SH, Zhu H, Hixson P, Mukhopadhyay S, Sun J, Cell Res 2023 Feb
- Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia.
- Palicharla VR, Hwang SH, Somatilaka BN, Legué E, Shimada IS, Familiari NE, Tran VM, Woodruff JB, Liem KF, Mukhopadhyay S, Mol Biol Cell 2023 Jan mbcE22100473
- 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
- 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
Honors & Awards
- Alex Lemonade Stand Foundation A-grant awardee
(2017-2021) - W.W. Caruth, Jr. Scholar in Biomedical Research
Endowed scholar, UT Southwestern (2013) - CPRIT Scholar in Cancer Research
(2012-2018)
Professional Associations/Affiliations
- American Society for Cell Biology. (2005)
- Member, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center. (2013)