Saikat Mukhopadhyay, MD, PhD

  • Recruited to: The University of Texas Southwestern Medical Center
  • Recruited from: Genetech
  • Award: First-Time, Tenure-Track Faculty Member

Dr. Saikat Mukhopadhyay is an assistant professor in the Department of Cell Biology at UT Southwestern Medical Center. He received his Ph.D. at Brandeis University, and then carried out his postdoctoral research at Genentech. The focus of his current research is to understand mechanisms of cellular signaling at the level of the primary cilia, and its relevance to human health and disease. The first cellular organelle to be described in biology, the primary cilium waslong mistaken as a vestigial appendage. The primary cilia are now considered as vital sensory organelles for detection and transmission of a broad range of chemical and mechanical signals in most cells. His current and future research aims at utilizing a variety of biochemical, cell biological and reverse genetic approaches to understanding signaling mediated by cilia, and dissecting their role during cell cycle control and carcinogenesis.

Dr. Mukhopadhyay was initially trained as a physician in Medial College, Calcutta, and Institute of Medical Sciences, Varanasi, India. During his M.D. years, he studied the role of tyrosine kinases in platelet signal transduction. He then joined Dr. Piali Sengupta’s laboratory in Brandeis University as a Ph.D. student. While studying the development of head neurons in the nematode C. elegans, he became interested in the distinctive morphology of the olfactory cilia.Using tools for real-time tracking of ciliary assembly in single neurons, he studied the differential requirements for building and maintaining specialized olfactory cilia. In addition, he discovered that the membrane architecture of the olfactory sensory cilia in C. elegans are patterned by coincidental signaling inputs, suggesting that cilia are not just static antennae, but organelles whose structures are remodeled by their signaling activities.

As a postdoctoral fellow in Dr. Peter Jackson’s lab in Genentech, he started utilizing an unbiased proteomic approach to build networks of proteins important in ciliary signaling. His initial studies involved studying the role of the tubby family proteins, a family of poorly understood proteins important in neural development and obesity. While generating the tubby family interactome, he discovered that the tubby-like protein, Tulp3 binds to a conserved ciliary complex, called the IFT-A complex. Primary cilia and intraflagellar transport (IFT), an ancient conserved trafficking mechanism within the cilia, are required for optimal sonic hedgehog (Shh) signaling during neural tube differentiation in vertebrates.Paradoxically, mutations in the IFT-A complex, which is implicated in retrograde IFT, cause increased Shh signaling in the neural tube. Similar to the IFT-A mutants, mutations in Tulp3, also exhibit increased Shh signaling in the neural tube.His studies on the Tulp3/IFT-A interaction suggested that in addition to its known role in retrograde transport, the core IFT-A sub-complex has a preciliary role in recruiting Tulp3 to the cilia, which in turn promotes trafficking of GPCRs to the cilia. Furthermore, using a candidate approach for ciliary GPCRs expressed early during development, he identified a ciliary GPCR, Gpr161, in repression of Shh signaling. The cAMP-activated protein kinase A (PKA) is pivotal in repressing Shh signaling by the processing of Gli transcription factors into repressors. However, more than a decade after this was first described, the cAMP regulating pathways that mediate this activation of PKA remain unknown. The processing of Gli repressor is blocked in the receptor knockout, and constitutive activity of the receptor results in increased cAMP levels. This suggests that Gpr161 could regulate PKA-mediated processing of Gli repressor via ciliary cAMP signaling.

At UT Southwestern Medical Center, Dr. Mukhopadhyay’s laboratory would utilize integrative approaches to dissect the role of this novel repression mechanism in Shh signaling, in cellular and organismal contexts, and particularly, in the context of Shh-mediated tumorigenesis. His group would also target this pathway for therapeutic intervention in Shh-dependent tumors, and for bypassing tumor resistance to available drugs.