Current projects

oogenesis regulation via stress response signaling


Reproduction is a systemic decision that requires extensive communication between tissues. Because of the high energetic cost of egg production, that decision is heavily influenced by nutrient availability. So, organisms need a way to sense metabolic status and correctly relay that information to the tissues that need it, like the ovaries. I found that adipose tissue (i.e., fat) plays a nutrient sensing role in reproductive regulation via the Integrated Stress Response (ISR). Read more about this phenotype here. We will continue to investigate how ISR signaling impacts cell biological functions within adipocytes under different conditions to influence the rate of egg production.

Fat tissue signaling + reproductive behavior


In addition to regulating egg production, ISR signaling presents as a “systemic” regulator of reproduction by also influencing the output of an essential reproductive behavior: ovulation. In flies we can use egg-laying behavior to readout ovulation rate, and in both flies and mammals ovulation is regulated via neural circuits that innervate the reproductive tract. In the absence of ISR signaling in the fat, ovulation is impaired and the result is an ovary that retains excess mature eggs (shown on the right). The rate of ovulation is incredibly sensitive to nutrient status; we will examine the neuronal regulation of reproduction by ISR signaling and how ovulation rate is controlled during both homeostasis and stress.

Sex differences in stress tolerance


Males and females have distinct physiological needs, many more than were previously appreciated. Among these, gamete production is a much more costly process (from an energetic standpoint) in females than in males. This means that metabolic pathways that influence lipid synthesis and storage are necessarily sexually dimorphic. I found that ISR signaling is higher in female tissue than fat tissue, and that this dimorphism renders female more resilient against death during nutrient-scarce conditions. We will further examine sex differences in the fat at the genetic/molecular level and how dimorphic gene/metabolite regulation impacts physiological functions like reproduction.

PUBLICATIONS

(under review) Nandakumar S, Grmai L, Vasudevan D. Integrated Stress Response Signaling: Mechanisms of homeostatic regulation in insects and mammals. The FEBS Journal. co-correspondence

Grmai L, Mychalczuk M, Arkalgud A, Vasudevan D (2024). Sexually dimorphic Atf4 expression in the fat underlies female stress tolerance in Drosophila melanogaster. bioRxiv. doi: 10.1101/2024.12.27.630478. co-correspondence
PMID: 39763862

Grmai L, Michaca M, Lackner E, Nampoothiri VP N, Vasudevan D (2024). Integrated Stress Response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation. Cell Reports.
PMID: 38457339
**an earlier version is viewable on bioRxiv,

Grmai L, Jimenez E, Baxter E, Van Doren M (2023). Steroid signaling controls sex-specific development in an invertebrate. bioRxiv. doi: 10.1101/2023.12.22.573099.
PMID: 38187640

Grmai L, Pozmanter C, Van Doren M (2022). The role of Sxl in Drosophila germline sexual identity instruction. Sexual Development. equal contribution
PMID: 35259743

Herrera SC, Sainz de la Maza D, Grmai L, Margolis S, Plessel R, Burel M, O’Connor M, Amoyel M, Bach EA (2021). Proliferative stem cells maintain quiescence of their niche by secreting the Activin inhibitor Follistatin. Dev Cell.
PMID: 34363758

Grmai L, Harsh S, Lu S, Korman A, Deb IB, Brodsky M, Wolfe S, Bach EA (2021). Transcriptomic analysis of feminizing somatic stem cells in the Drosophila testis reveals putative downstream effectors of the transcription factor Chinmo. G3. equal contribution   
PMID: 33751104

Grmai L, Hudry B, Miguel-Aliaga I, Bach EA (2018). Chinmo prevents transformer alternative splicing to maintain male sex identity. PLOS Genetics.
PMID: 29389999 

Zoranovic T, Grmai L, Bach EA (2013). Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway. JAK-STAT.
PMID: 24069565 

Chornoguz O, Grmai L, Sinha P, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S (2011). Proteomic pathway analysis reveals inflammation increases myeloid-derived suppressor cell resistance to apoptosis. Mol Cell Proteomics.
PMID: 21191032